Heterocyclic Compounds as Sweetener Enhancers

ABSTRACT

The present invention is directed to the use of a compound of Formula I 
     
       
         
         
             
             
         
       
     
     and physiologically acceptable salts thereof wherein G 1 , G 2 , G 3 , R 1 , R 2 , R 7 , R 3 , R 4 , and R 5  are defined herein. Compounds according to Formula I can be used to enhance a sweet taste produced by a tastant. The invention is also directed to compositions comprising a compound according to the above formula. Other aspects of the invention provide methods, compounds, and compositions for improved food products wherein the food product comprises a compound according to Formula I and a reduced amount of a sweet tastant.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.11/843,411, filed Aug. 22, 2007, which claims the benefit of U.S.Provisional Application No. 60/839,118, filed Aug. 22, 2006, which isherein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the use of compounds of Formula I forenhancing a sweet taste, masking an unpleasant taste by creating a sweettaste, and related uses. The invention is also directed to, among otherthings, compositions comprising a compound of Formula I that can be usedin pharmaceutical, food, and other products as a sweetener enhancer oras a taste masking agent. In certain aspects, the invention providesmethods and compositions for enabling one to prepare consumableproducts, such as food and pharmaceutical products, which retain adesired sweetness but contain lower amounts of sweetener, such as sugar,and in some cases fewer calories.

2. Background Art

Taste perception plays a critical role in the nutritional status andsurvival of both lower and higher animals (Margolskee, R. F., J. Biol.Chem. 277:1-4 (2002); Avenet, P. and Lindemann, B., J. Membrane Biol.112:1-8 (1989)). The ability to taste has significance beyond providingpeople with pleasurable culinary experiences. For example, the abilityto taste allows us to identify tainted or spoiled foods, and providessatisfying responses that may be proportionate to caloric or nutritivevalue.

There are generally considered to be only four or five categories ofbasic taste: sweet, sour, bitter, acid, and “umami” (the Japanese worddescribing the taste of monosodium glutamate; Hemess, M. S. &Gilbertson, T. A., 1999, Annu. Rev. Physiol. 61:873-900). These can besub-classified as the appetitive tastes, such as salty, sweet and umami,which are associated with nutrient-containing foods, and the bitter andsour tastes elicited by toxic compounds.

The anatomic basis for the initial events of taste is the taste receptorcell (“TRC”), located in clusters referred to as “taste buds”(Lindemann, supra). Taste buds are distributed throughout the oralcavity, including the tongue as well as extra-lingual locations (seeHemess and Gilbertson). In the human tongue, taste buds are organizedinto three specialized types of specialized structures, namelyfungiform, foliate, and circumvallate papillae. Each taste bud comprisesbetween about 50 and 100 individual cells grouped into a cluster that isbetween 20 and 40 microns in diameter. Nerve fibers enter from the baseof the taste bud and synapse onto some of the taste receptor cells.Typically, a single TRC contacts several sensory nerve fibers, and eachsensory fiber innervates several TRCs in the same taste bud (Lindemann,supra).

When a subject ingests a tastant, and that tastant encounters a tastereceptor cell in the appropriate concentration, an action potential isproduced which, via synapses with primary sensory neurons, communicatesthe signal registered by the receptor, via afferent nerves, to theappropriate region of the sensory cortex of the brain, resulting in theperception of a particular taste by the subject.

Although taste perception is a vital function, sometimes it is useful tomodify certain tastes. For example, many active pharmaceuticalingredients of medicines produce undesirable tastes, such as a bittertaste. Masking the bitter taste produced by the medicine by adding asweetener enhancer may lead to improved acceptance by the patient.

Traditionally, sweeteners and flavorants have been used to mask thebitter taste of pharmaceuticals. The sweetener or flavorant is known toactivate other taste pathways and at sufficiently high concentrationthis serves to mask the bitter taste of the pharmaceutical. Using largeconcentrations of sweeteners such as table sugar (sucrose) isundesirable because of the high number of calories and because it cannotbe administered to diabetics. Artificial sweeteners such as aspartameand saccharin do not have these drawbacks but can have an undesirableaftertaste or present safety concerns if used in large quantities.

A number of other methods have been suggested to inhibit, alter, or maskunwanted tastes. However, the presently available compounds are lackingin desirable characteristics.

Another area in which enhancing sweet taste would be useful is inencouraging food intake in subjects who have an impaired ability totaste or in patients who have lost their appetites. Studies have shownincreased food intake as palatability increased. Sorensen, et al., Int.J. Obes. Relat. Metab. Disord. 27(10):1152-66 (2003). For instance,certain drugs, such as antihypertensives and antihyperlipidemics, havebeen reported to produce untoward alterations in taste and may result indecreased food intake. Doty, et al., J Hypertens. 21(10):1805-13 (2003).Taste impairment has also been associated with radiation treatments forhead and neck cancer and this taste impairment has been considered to beone of the factors associated with reduces appetite and altered patternsof food intake. Vissink, et al., Crit. Rev. Oral Biol. Med. 14(3):213-25(2003). Decreased food consumption has also been correlated with loss oftaste sensations in the elderly. Shiffman, S. S., J. Am. Med. Ass'n278(16):1357-1362 (1997). Enhancing the sweet taste of food could leadto increased consumption of foods containing these enhancers.

Therefore, there exists a need for compounds that can effectivelyenhance a sweet taste, preferably without exhibiting one or more of thelimitations of the prior art sweetening agents.

BRIEF SUMMARY OF THE INVENTION

A first aspect of the present invention is directed to a method ofenhancing a sweet taste, comprising administering to a subject a sweettastant and one or more compounds of Formula I, or a physiologicallyacceptable salt thereof.

In certain aspects of the invention, as described further below, themethods and compositions of the present invention allow one to createfood products with sufficient sweetness but with reduced levels of knownsweet tastants, such as sugar. These methods also enable one to preparean improved food product with the same level of sweetness as theoriginal food product but with reduced calories from the caloricsweetness.

An additional aspect of the present invention is directed to a method ofenhancing a sweet taste of a food product, comprising administering to asubject a food product comprising a sweet tastant and one or morecompounds of Formula I, or a physiologically acceptable salt thereof.

An additional aspect of the present invention is directed to a method ofenhancing a sweet taste of a pharmaceutical, comprising administering toa subject a pharmaceutical comprising a sweet tastant and one or morecompounds of Formula I, or a physiologically acceptable salt thereof.

An additional aspect of the present invention is directed to a method ofincreasing the palatability of food and its intake comprisingadministering to a subject a food product comprising a sweet tastant andone or more compounds of Formula Ito a subject in need of suchtreatment.

An additional aspect of the present invention is directed to a method ofmasking an undesirable taste of a food product, comprising administeringto a subject a food product comprising a sweet tastant and one or morecompounds of Formula I, or a physiologically acceptable salt thereof.

An additional aspect of the present invention is directed to a method ofmasking an undesirable taste of a pharmaceutical, comprisingadministering to a subject a pharmaceutical comprising a sweet tastant,one or more compounds of Formula I, or a physiologically acceptable saltthereof.

An additional aspect of the present invention is directed to a foodproduct comprising a sweet tastant and one or more compounds accordingto Formula I or a physiologically acceptable salt thereof.

An additional aspect of the present invention is directed to apharmaceutical composition comprising an active agent, optionally one ormore pharmaceutically acceptable carriers, a sweet tastant, and one ormore compounds of Formula I or a physiologically acceptable saltthereof.

These and additional aspects of the present invention are described indetail below.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, serve to explain the principles of the inventionand to enable a person skilled in the pertinent art to make and use theinvention.

FIG. 1 illustrates the generation of the TRPM5 membrane potential dyefluorescent response in transfected HEK 293 cells. It utilizes afluorescence Intentsity Plate Reader (FLIPR) and carbachol to cause aCa++ response and trigger TRPM5.

FIG. 2 illustrates a cell-based assay utilizing cloned mTRPM5 fordetecting active compounds. FIG. 2 demonstrates that onlyTRPM5-transfected cells generate a membrane potential response while allcells, both sham and transfected, generate Ca²⁺ signals.

FIG. 3 illustrates the selective enhancement of TRPM5 activity by threedifferent concentrations of the compound of Example 8. The upper leftgraph of FIG. 3 shows the effect of 1, 3, 10, and 30 micromolar (μM) ofthe compound of Example 8 on TRPM5 activity in hTRPM5-HEK293 cells, asmeasured in the fluorescent assays described herein. The upper rightgraph of FIG. 3 shows the effect of 1, 3, 10, and 30 μM of the compoundof Example 8 at on TRPM5 activity in CHO cells as measured in thefluorescent assays described herein. The lower left graph of FIG. 3illustrates a calcium counterscreen assay, in which the hTRPM5-HEK293cells were loaded with a calcium sensitive dye and stimulated by ATP tocheck to see if the compound of Example 8 blocks the GPCR-mediatedcalcium activated step. The lower right graph of FIG. 3 illustrates aKCl counterscreen, in which 1, 3, 10, and 30 μM of the compound ofExample 8 is added to hTRPM5-hTRPM5-HEK293 cells, stimulated by KClinstead of ATP to determine whether the compound was a specific ionchannel enhancer. In these experiments TRPM5 was stimulated by anotherGPCR present in HEK and CHO cells using ATP as agonist.

FIG. 4 illustrates the enhancement of TRPM5 activity (membrane potentialresponse) as a function of ATP concentration with several differentcompounds. The compounds had little effect on calcium dye response toincreasing ATP agonist levels. The results show selective enhancement ofTRPM5 activity by the compounds of the invention at low concentrationsof GPCR agonist ATP (a surrogate tastant). The left graph of FIG. 4shows the effect of the addition of 30 micromolar of the compounds ofExamples 1-3,5,10 and 18 on the ATP concentration-effect function formembrane potential in hTRPMS-HEK293 cells, as measured by thefluorescent assay described herein. The right graph shows the effect ofthe addition of a compound of the invention at 30 micromolar on ATPconcentration-effect function for intracellular calcium in hTRPM5-HEK293cells, as measured in the fluorescent assays described herein.

FIG. 5 illustrates the results of the selective enhancement of TRPM5activity by the compounds of Examples 1-3, 5, 10, and 18. The resultsindicate a dramatic increase (>10×) of TRPM5 activity at sub-optimal ATPagonist concentrations (0.1 μM). At low ATP concentration, i.e. 0.1 uM,the ratio of ATP signal alone vs. the signal in the presence of thecompounds in some cases is greater than 10 fold.

FIG. 6 illustrates stimulation of TRPM5 current when TRPM5 transfectedHEK 393 cell are exposed to 10 μM boluses (red bars) of the compound(Example 10) in a flow-through electrophysiological apparatus. The leftgraph of FIG. 6 shows no activation by compound in the absence ofcalcium. The central graph of FIG. 6 show a large >5 nA current (+80 mV)pulses in response to boluses of the compound at a calcium concentrationof 300 nm. Note that the current drops off when the exposure of compoundis stopped, i.e. the compound is washed away. The far right graph showsa stimulation of current by compound at 30 μm calcium. While there isfurther stimulation of the TRPMS current by compound at 30 uM, it is notas dramatic as at 300 nn Ca++. Note that no significant current was seenin non-transfected, sham HEK cells (not shown).

FIG. 7 shows dose-response curve for enhancing the activity of TRPMSprotein in hTRPMS-HEK293 cells. The graphs show the effects of thecompounds of Examples 1, 2, 3, and 10.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds and compositions that areuseful, for example, for enhancing sweet tastes. The methods of thepresent invention enable one to use a known sweetening agents, or sweettastants, in a reduced amount combined with a compound according toFormula I, or any of the specific subgroups or specific compoundsdescribed herein, in order to achieve the same level of sweetness whenthe known sweet tastant is used alone in the traditional amount. By wayof brief example, a common carbonated cola beverage may contain about 20to 30 grams of sugar (e.g., fructose) and about 100 calories per 8 ounceserving. The present invention enables one to prepare a similar colabeverage with substantially reduced sugar and caloric content but withthe same level of sweetness. The compounds identified in here, e.g.,according to Formula I, enhance the sweet taste produced by the reducesugar content, thereby creating an enhanced sweet taste based on thereduced level of sweet tastant, e.g., table sugar.

Other aspects of the present invention are described in detail herein.

Methods of Use

A first aspect of the present invention is directed to a method ofenhancing a sweet taste, said method comprising administering to asubject a sweet tastant and a compound of Formula I or a physiologicallyacceptable salt thereof,

wherein

G¹, G², and G³ are independently selected from N, S, and C;

R¹ and R² are independently absent or selected from hydrogen, C₁₋₆alkyl, halogen, nitro, optionally substituted C₆₋₁₄ aryl, optionallysubstituted 5-14 membered heteroaryl, optionally substituted 5- to14-membered heteroaryloxy, optionally substituted 5-14 memberedheteroarylthio, Ar-Q, optionally substituted (CH₂)_(n)C(═O)—O—R^(2a),and optionally substituted (CH₂)_(n)C(═O)aryl, or R¹ and R², togetherwith the G³ and the carbon atom to which R¹ is attached, form a C₆₋₁₄aryl or 5- to 14-membered heterocycle, each of which is optionallysubstituted; or if the bond to R¹ and/or R² is a double bond, then R¹and R² are independently selected from ═NH and ═O;

R³ is selected from H, C₁₋₆ haloalkyl, C₁₋₆ alkyl, oxo, ═NH, optionallysubstituted C₆₋₁₄ aryl, and optionally substituted 5-14 memberedheterocycle, or R³ is L¹-R³¹, such as ═Z¹-(CH₂)_(n)—Z²—R³¹ or;

R⁴ is absent or is selected from the group consisting of H, C₁₋₆ alkyl,C₁₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆hydroxyalkyl, optionally substitutedC₆₋₁₄ aryl, and optionally substituted (CH₂)_(n)C(═O)aryl, or when thebond to R⁴ is a double bond, R⁴ is ═O; and

R⁵ is either absent or is selected from hydrogen, C₁₋₆ alkyl, andoptionally substituted phenyl amide;

R⁷ is either absent or selected from H and C₁₋₆ alkyl;

R^(2a) is C₁₋₆ alkyl;

R³¹ is H, C₁₋₆ alkyl, C₁₋₆ alkenyl, optionally substituted phenyl,amino, C₁₋₆ alkylamino, or C₁₋₆ dialkylamino;

Z¹ is selected from ═N, —NH, O, and S;

Z² is O, S, C(═O), C(═S), —C(═O)—O, C(═S)—O, —C(═O)—NH— or —C(═S)—NH;

L¹ is linker containing 1 to 30 carbon and/or heteroatoms;

Q is CH₂, O, NH, or S;

Ar is optionally substituted aryl or optionally substituted heteroaryl;and

n is 0 to 10.

Preferred groups of compounds within Formula I to be used in the methodsof the present invention include

wherein R¹R⁵ are defined as above.

Each of the bonds in the five-membered ring of Formula I may be a singleor double bond. In one embodiment, the ring formed from G¹, G², and G³contains only single bonds. In another embodiment, the ring formed fromG¹, G², and G³ contains one or two double bonds.

In one embodiment, one of G¹, G², and G³ is carbon, and the others areselected from N or S. In a further embodiment, G³ is carbon, and G¹ andG² are selected from N or S. In a further embodiment, G³ is carbon, oneof G¹ and G² is N, and the other is S. In a further embodiment, G³ iscarbon, and both G¹ and G² are N. In a further embodiment G² is carbon,and G¹ and G³ are selected from N or S

In another embodiment, one of G¹, G², and G³ is S, and the others are N.In another, G¹, G², and G³ are N. In another, G¹ is S, and G² and G³ arecarbon.

In another embodiment, G¹, G², and G³ are selected to form one of thefollowing groups:

In one embodiment, R¹ and R² are independently optionally substitutedC₆₋₁₀ aryl, such as phenyl or naphthyl. In another embodiment, R¹ and/orR² are an optionally substituted 5-10 membered, preferably 5-7 membered,heteroaryloxy or heteroarylthio. The heteroaryl includes but is notlimited to pyridyl, pyrimindinyl, imidazolyl, tetrazolyl, furanyl,thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl, andbenzothiazolyl, each of which is optionally substituted. In otherinstances, the heteroaryl group is a 5-10 membered, preferably 5-7membered, nitrogen-containing heteroaryl.

Another subset of R¹ and R² includes a substituted aryl or heteroarylgroup having 1-3 substituents independently selected from the groupconsisting of amino, hydroxy, nitro, halogen, cyano, thiol, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₁₋₆alkylenedioxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ aminoalkyl, C₁₋₆hydroxyalkyl, C₂₋₆ hydroxyalkoxy, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino,C₂₋₆alkoxycarbonyl, carboxy, C₂₋₆ carboxyalkoxy, and C₂₋₆ carboxyalkyl.

In another embodiment, R¹ and R² are independently a C₃₋₁₀ ester or C₁₋₆alkyl-C(═O)—Ar, wherein Ar is an optionally substituted phenyl. In afurther embodiment, Ar is optionally substituted by 1-3 substituentselected from the group consisting of amino, hydroxy, nitro, halogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₁₋₆ alkoxy.

In another embodiment, the bond to R¹ and/or R² is a double bond, and R¹and R² are independently selected from ═NH and ═O. More specifically,both the bond from the ring to R¹ or R² can be either a single bond or adouble bond. When the bond to R¹ is a single bond, R¹ is selected fromhydrogen, C₁₋₆ alkyl, halogen, nitro, optionally substituted C₆₋₁₄ aryl,optionally substituted 5- to 14-membered heteroaryloxy, optionallysubstituted 5-14 membered heteroarylthio, optionally substitutedCH₃(CH₂)_(n)C(═O)—O—R, and optionally substituted CH₃(CH₂)_(n)C(═O)aryl.When the bond to R¹ is a double bond, R¹ is either NH or O. R² isdefined likewise.

In another embodiment, R¹ and R², together with the G³ and the carbonatom to which R¹ is attached, form an optionally substituted C₆₋₁₄ aryl,such as phenyl or naphthyl, or an optionally substituted 5-14 memberedheterocycle, such as but not limited to pyridyl, pyrimindinyl,imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl,quinolinyl, pyrrolyl, benzimidazolyl, diazole, triazole, thiazole,thiadiazole, thiatriazole, benzothiophene, benzothiopyran, andbenzopyran. In other instances, the heterocycle group is anitrogen-containing and/or sulfur-containing heterocycle.

In another subset of R¹ and R², R¹ and R², together with the G³ and thecarbon atom to which R¹ is attached, form a C₆₋₁₄ aryl or a 5-14membered heterocycle having 1-3 substituents independently selected fromthe group consisting of amino, hydroxy, nitro, halogen, cyano, thiol,oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆alkenyloxy, and optionally substituted C₆₋₁₄ aryl. In a furtherembodiment, the ring formed from R¹ and R² together with the G³ and thecarbon atom to which R¹ is attached is substituted by a C₆₋₁₄ aryl,optionally containing one or more C₁₋₆ alkyl, halo, C₁₋₆ haloalkyl ornitro groups.

Alternatively, R¹ and R² may be independently Ar-Q, wherein Q is CH₂, O,NH, or S, and Ar is optionally substituted aryl or optionallysubstituted heteroaryl. Preferably, Ar is optionally substituted C₆₋₁₄aryl or optionally substituted 5-14 membered heteroaryl. Suitable Ar-Qgroups include optionally substituted 5- to 14-membered heteroaryloxyand optionally substituted 5-14 membered heteroarylthio.

In another embodiment, G¹, G², and G³ along with R¹, R², form aheterocycle ring system selected from:

In one embodiment, R³ is optionally substituted C₆₋₁₀ aryl, such asphenyl or naphthyl. In another embodiment, R³ is optionally substituted5-10 membered, or preferably 5-7 membered, heterocycle, such as, but notlimited to pyrrolidyl, piperidyl, diazacyclopentyl, triazacyclopentyl,azacyclohexyl, diazacyclohexyl, triazacyclohexyl, azacycloheptyl,diaazacycloheptyl, triazacyclohepyl, azacyclopentenyl,diazacyclopentenyl, triazacyclopentenyl, azacyclohexenyl,diazacyclohexenyl, triazacyclohexenyl, azacycloheptenyl,diazacycloheptenyl, and triazacycloheptenyl. In a further embodiment, R³is selected from a diazacycheptyl and a diazacyclohexenyl. In a furtherembodiment, R³ is either 1,4-diazacycloheptyl or1,5-diazacyclohex-2-en-3-yl.

Another subset of R³ includes a substituted aryl group having 1-3substituents independently selected from the group consisting of amino,hydroxy, nitro, halogen, cyano, thiol, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, and C₃₋₆ alkenyloxy. In a further embodiment R³is substituted by one or more of nitro, halogen, C₁₋₆ alkyl, and C₁₋₆alkoxy.

Another subset of R³ includes a substituted heterocycle group having 1-4substituents independently selected from the group consisting of amino,hydroxy, nitro, oxo (i.e. ═O), halogen, cyano, thiol, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₁₋₆ alkyl-Ar,Ar, and —C(═O)—NH—Ar, wherein Ar is an optionally substituted phenyl. Ina further embodiment, Ar is optionally substituted by 1 to 3substituents selected from the group consisting of nitro, halogen, C₁₋₆alkyl, and C₁₋₆ alkyloxy.

In another embodiment, R³ is L¹-R³¹, wherein L¹ is a linker containing 1to 30 carbon atoms and/or heteroatoms and R³¹ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₆ alkenyl, optionally substitutedphenyl, amino, C₁₋₆ alkylamino, or C₁₋₆ dialkylamino.

The linker L¹ can comprise various carbon- and/or heteroatom-containingmoieties. The size of the linker can be from 1 (e.g., CH₂, O, NH, etc.)to 30 carbon atoms and/or heteroatoms. The number of carbon atoms and/orheteroatoms does not, of course, include hydrogen atoms. In certaininstances, the linker is an alkylene linker containing only carbon andhydrogen atoms. In other instances, the linker is a heteroalkylenelinker containing carbon and hydrogen atoms and also one or moreheteroatoms, such as nitrogen, oxygen, and sulfur. The linker can bestraight-chained or branched. The linker may comprise one or more cyclicgroups, either as the whole linker or as part of the linker group. Thecyclic group may be carbocyclic or heterocyclic. The linker may beoptionally substituted.

The linker group of L¹ may saturated or unsaturated. Certain linkergroups may contain one or more double bonds.

In a preferred embodiment, the linker contains at least one heteroatom,and contains 2-15, preferably 2-10, carbon atoms and heteroatoms. Othersuitable linker groups for L¹ include ═N—CH₂C(O)OCH₂—, —SCH₂CH₂O—,═NC(S)NHCH₂CH═, —C(O)NH—, and —NHC(O)CH₂—. Alternatively, L¹ may be-Het-C(O)—NH— wherein Het is a 5- to 7-membered nitrogen-containingheterocycle

In other instances, the linker group comprises a 5-7 membered cyclic,preferably heterocyclic moiety. The linker group may contain 1-4,preferably 1-2 heteroatoms.

In another instance. L¹ is one of the following linker groups:

In another embodiment, L¹-R³¹ is ═Z¹—(CH₂)_(n)—Z²—R³¹ wherein:

Z¹ is N, NH, O, or S;

n is 0 to 4, preferably 1 or 2;

Z² is O, S, C(═O), C(═S), —C(═O)—O, C(═S)—O, —C(═O)—NH— or —C(═S)—NH;and

R³¹ is selected from C₁₋₆ alkyl, C₁₋₆ alkenyl, optionally substitutedphenyl, and

—(CH₂)—NR′R″ wherein R′ and R″ are selected from H and C₁₋₆ alkyl.

In a further embodiment, R³¹ is a substituted aryl, such as substitutedphenyl containing 1 to 3 substituents independently selected from thegroup consisting of nitro, halogen, hydroxy, C₁₋₆ haloalkyl, C₁₋₆ alkyl,and C₁₋₆ alkyloxy.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁴ is absent, H, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl;R⁵ is absent, H, or C₁₋₆ alkyl; R^(a) is H or C₁₋₆ alkyl; and G¹ and G²are independently C, N, or S.

A preferred compound of Formula I for use in the methods of the presentinvention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁵ is H or C₁₋₆ alkyl; G is N or S; and R^(a)represents H or C₁₋₆ alkyl.

Another preferred compound for use in the methods of the presentinvention is a compound according to the formula:

wherein G² is N or S; R⁵ is H or C₁₋₆ alkyl; G⁴ is N, S, or O; L² is alinker containing 1-10 carbon and/or heteroatoms; and R³¹ is H oroptionally substituted phenyl.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁴ is H, C₁₋₆ hydroxyalkyl; R⁵ is absent; andR^(a) is H or C₁₋₆ alkyl.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R¹ and R² are independently selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S,or CH₂, and Ar is an optionally substituted aryl or optionallysubstituted heteroaryl; R³ is H or C₁₋₆ alkyl; R⁴ is absent, H, or C₁₋₆alkyl; R⁵ is absent, H, or C₁₋₆ alkyl; and G¹ is C or N; and G² is N orS.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R¹ and R² are independently selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S,or CH₂, and Ar is an optionally substituted aryl or optionallysubstituted heteroaryl; R³ is H or C₁₋₆ alkyl; R⁴ is H or C₁₋₆ alkyl;and R⁵ is absent.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R¹ and R² are independently selected from the group consistingof H, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S,or CH₂, and Ar is an optionally substituted aryl or optionallysubstituted heteroaryl; R³ is H or C₁₋₆ alkyl; R⁴ is absent; and R⁵H orC₁₋₆ alkyl.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁵ is H or C₁₋₆ alkyl; G² is C, N, or S; and Cyrepresents an optionally substituted fused ring comprising 5-10,preferably 5-7, carbon atoms and/or heteroatoms.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; and Cy represents an optionally substituted fusedring comprising 5-10, preferably 5-7, carbon atoms and/or heteroatoms.Alternatively, R³ represents optionally substituted aryl, such asphenyl, and the Cy group contains one or more nitrogen and/or sulfuratoms.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; and Cy represents an optionally substituted fusedring comprising 5-10, preferably 5-7, carbon atoms and/or heteroatoms.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁵ is H or C₁₋₆ alkyl; G² is C, N, or S; G³ is Cor N; R⁴ is H or absent; and Cy represents an optionally substitutedfused ring comprising 5-10, preferably 5-7, carbon atoms and/orheteroatoms.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R³ is L¹-R³¹; R⁴ is H or absent; R⁵ is H or C₁₋₆ alkyl; G² is Cor N; and Cy represents an optionally substituted fused ring comprising5-10, preferably 5-7, carbon atoms and/or heteroatoms.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to the formula:

wherein R¹ is C₁₋₆ alkyl or optionally substituted C₆₋₁₀ aryl; R² is Hor absent; R³ is L¹-R³¹; R⁴ is H or absent; R⁵ is H or absent; R³¹ is alinker, preferably comprising 2 to 20 carbon atoms and/or heteroatoms;G¹ is N or C; G² is N or S; and G³ is N or C.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to formula:

wherein R¹ is C₁₋₆ alkyl or optionally substituted C₆₋₁₀ aryl; R³ isL¹-R³¹; R⁴ is H or absent; R⁵ is H or absent; G¹ is N or C; and G² is Nor S.

Another preferred compound of Formula I for use in the methods of thepresent invention is a compound according to formula:

wherein R¹ is C₁₋₆ alkyl or optionally substituted C₆₋₁₀ aryl; R⁴ is Hor absent; R⁵ is H or absent; G¹ is N or C; G² is N or S; G⁴ is NH, S,or O; L¹ is a linker containing 1-10 carbon atoms and/or heteroatoms;and R³¹ is H, NR^(a)R^(b) or optionally substituted phenyl, whereinR^(a) and R^(b) are independently H or C₁₋₆ alkyl.

In a first subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula II

wherein:

R⁴ is H, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl;

R³¹ is H, C₁₋₆ alkyl, C₁₋₆ alkenyl, or optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy and hydroxyl;

R^(a) is H or C₁₋₆ alkyl, preferably H;

G¹ is S or N;

Z¹ is S or N;

Z² is —C(═O)—O, —C(═S)—O—, —O—, —S—, —C(═O)—NH—, or —C(═S)—NH—; and

n is 0 to 4, preferably 1 or 2.

In one embodiment within the first subclass, the compound of Formula IIis selected from a compound of Formula III:

wherein R⁴ is H, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl;

R³¹ is selected from H, C₁₋₆ alkyl, and C₁₋₆ alkenyl;

R^(a) is H or C₁₋₆ alkyl, preferably H;

Z³ is O or S;

Z⁴ is O, S, or NH; and

n is 0 to 3.

In a further embodiment within the first subclass, the compound ofFormula III is selected from a compound of Formula IV:

wherein R⁴ is selected from H and C₁₋₆ alkyl;

R³¹ is H or C₁₋₆ alkyl;

R^(a) is H or C₁₋₆ alkyl; and

n is 0 to 3.

In a further example of this embodiment, R³¹ is alkyl, preferably ethyl.In another example, R⁴ is alkyl, preferably methyl. In another, n is 1.In another, R^(a) is hydrogen

In a further embodiment within the first subclass, the compound ofFormula III is selected from a compound of Formula V:

wherein R² is H or C₁₋₆ alkyl;

R³ is H, C₁₋₆ alkyl, or C₁₋₆ alkenyl;

R⁴ is selected from H and C₁₋₆ alkyl; and

n is 0, 1, 2, or 3.

In one example of this embodiment, R⁴ is alkyl, preferably methyl. Inanother example, R^(a) is hydrogen. In another, n is zero. In another,R³¹ is alkenyl, preferably 2-propenyl.

In a further embodiment within the first subclass, the compound ofFormula II is selected from a compound of Formula VI

wherein R⁴ is selected from H, C₁₋₆ alkyl, and C₁₋₆ hydroxyalkyl;

R^(a) is H or C₁₋₆ alkyl;

R^(b) is C₁₋₆ alkyl, C₁₋₆ alkyloxy, or hydroxy;

n is 0 to 3; and

p is 0 to 5.

In one example of this embodiment within the first subclass, R^(a) ishydrogen. In another, R⁴ is hydroxyalkyl, preferably 2-hydroxyethyl. Inanother, R⁴ is hydrogen. In another, n is 2 or 3. In another embodiment,R^(b) is alkyloxy, preferably methoxy. In another, the phenyl ringcontaining (R^(b))_(p) is 2,6-dimethoxyphenyl or 2-methoxyphenyl.

In a second subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula VIII:

wherein G¹ is N or S;

Q is N or C;

R³ is H or optionally substituted phenyl, preferably optionallysubstituted by one or more selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxyl, halogen, and nitro;

R⁵ is H when G¹ is N, or otherwise is absent;

R⁶ is selected from H and C₁₋₆ alkyl; and

R⁷ is selected from H, C₁₋₆ alkyl, and optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl or nitro, or, when Q is N, R⁷ is absent.

In one embodiment within this second subclass, R³ is hydrogen. Inanother embodiment, R³ is an optionally substituted phenyl, preferablyoptionally substituted by one or more of halogen or nitro. In another,R⁷ is hydrogen or tolyl.

In another embodiment within this second subclass, the compound ofFormula VIII is selected from a compound of Formula IX,

wherein R³ is H, C₁₋₆ alkyl, or optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl, or nitro; and R⁷ is selected from H, C₁₋₆alkyl, and optionally substituted phenyl, preferably optionallysubstituted by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxylor nitro.

In a further example of this embodiment, R³ is hydrogen. In another, R⁷is an optionally substituted phenyl, preferably optionally substitutedby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl or nitro;or R⁷ is a tolyl group.

A further embodiment within this second subclass is a compound ofFormula IX, wherein: R³ is H or C₁₋₆ alkyl, preferably H; and R⁷ isselected from H, C₁₋₆ alkyl, and optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl or nitro, or preferably R⁷ is an optionallysubstituted phenyl. In one embodiment, R⁷ is a tolyl group.

In a further embodiment within this second subclass, the compound ofFormula VIII is selected from a compound of Formula X:

wherein R³ is selected from H, C₁₋₆ alkyl, and C₆₋₁₀ aryl, preferablyoptionally substituted phenyl, preferably optionally substituted withone or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, or nitro; R⁵is H; and R⁶ is selected from H and C₁₋₆ alkyl.

In a further embodiment within this second subclass, the compound ofFormula VIII is selected from a compound of Formula X, wherein R³ isC₆₋₁₀ aryl, preferably phenyl, optionally substituted with one or moreof C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, or nitro; and R⁶ is H or C₁₋₆alkyl. In one embodiment, R³ is substituted by one or more halogenand/or a nitro groups. In another embodiment, R³ is3-nitro-4-chlorophenyl or C₁₋₆ alkyl, preferably ethyl.

In a third subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XI:

wherein R³ is H or C₁₋₆ alkyl, preferably hydrogen;

R⁵ is H or C₁₋₆ alkyl, preferably hydrogen;

Ar is a 5- to 10-membered aryl or heteroaryl group, preferably a 5- or6-membered nitrogen containing heteroaryl group, optionally substitutedwith one or more groups independently selected from the group consistingof NO₂, halogen, C₁₋₆ alkyl, and C₁₋₆ hydroxyalkyl;

Q is O or NH;

R^(b) is H or C₁₋₆ alkyl; and

n is 0 to 3.

In one embodiment of this third subclass, R¹ is a C₁₋₆ alkyl, preferablymethyl. In another embodiment Q is oxygen. In another, Ar is a 5- or6-membered nitrogen containing heteroaryl group, preferably pyridyl. Inanother, R² is nitro. In another, n is one.

In another embodiment within this third subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XII:

wherein R³ is H or C₁₋₆ alkyl;

each occurrence of R^(a) is independently selected from the groupconsisting of NO₂, halogen, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl;

R^(b) is H or C₁₋₆ alkyl; and

n is 0 to 3.

In one example of this embodiment, R¹ is C₁₋₆ alkyl, preferably methyl.In another, R³ is hydrogen. In another, n is 1. In another, R² is nitro.In another, the pyridine ring is attached to the oxygen atom at the2-position.

In a fourth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XIII

wherein R¹ is an optionally substituted phenyl, preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkyloxy, halogen, hydroxyl andnitro;

R³ is Het-C(O)—NH—R³¹;

Het is a 5- to 7-membered nitrogen-containing heterocycle; and

R³¹ is an optionally substituted phenyl, preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkyloxy, halogen, and NO₂.

In one embodiment of this fourth subclass, R¹ is unsubstituted phenyl.

The Het group can be any 5- to 7-membered nitrogen-containingheterocycle, including heteroaryl groups. The Het group, in certainembodiments, contains 1 to 4, preferably 1 or 2 nitrogen atoms in thering. Suitable Het groups include, but are not necessarily limited to,piperidine, piperizine, pyrrolidine, azepine, and morpholine.

By way of example, a suitable group of compounds for use within thisfourth subclass is a compound of Formula XIII

wherein R¹ is phenyl optionally substituted, for example, by one or moreof C₁₋₆ alkyl, C₁₋₆ alkyloxy, halogen, and/or NO₂, preferably R¹ isphenyl; and R³¹ is phenyl optionally substituted, for example, by one ormore of C₁₋₆ alkyl, C₁₋₆ alkyloxy, halogen, hydroxyl and/or NO₂,preferably R³¹ is unsubstituted phenyl.

In a fifth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XIV:

wherein R¹ is H, C₁₋₆ alkyl, halogen, or NO₂;

R³ and R⁴ are independently H or C₁₋₆ alkyl;

Q is S, N, or O, preferably S; and

Het is a 5- to 6-membered heteroaryl, preferably a nitrogen-containingheteroaryl, optionally substituted with one or more substituentsselected from the group consisting of nitro and halogen.

Suitable Het groups include pyridinyl, pyrrolyl, and pyrimindyl. Forexample, Het can be a pyridyl group and, in particular, wherein thepyridyl group is attached to Q at the 2-position. In one embodiment, theHet group is substituted with a halogen, preferably chlorine. In oneembodiment, n is 1. In another embodiment, Het is a 5-chloropyridylgroup attached to Q at the 2-position. In another embodiment, R¹ isnitro. In another embodiment, R³ is alkyl, preferably methyl. In anotherembodiment, R⁴ is alkyl, preferably ethyl.

In a sixth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XV:

wherein R¹ and R³ are independently optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl, or nitro;

R⁴ is absent, O, or C₁₋₆ alkyl; and

R² and R⁷ are independently C₁₋₆ alkyl.

In a further embodiment within the sixth subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XVI:

wherein R¹ and R³ are independently optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl, or nitro; and R² and R⁷ are independently isH or C₁₋₆ alkyl.

In a further embodiment within the sixth subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XVI wherein: R¹ and R³ arephenyl; and R² and R⁷ are independently H or C₁₋₆ alkyl.

In a seventh subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XVII:

wherein R¹ is H or C₁₋₆ alkyl;

R² is H;

R³ is C₁₋₆ alkyl, H, oxo, or ═NH;

R³¹ is optionally substituted phenyl, preferably optionally substitutedby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, and nitro;and

n is 0 to 3.

In one embodiment, R³¹ is a phenyl substituted by a nitro group,preferably R³¹ is 3-nitrophenyl. The bond between R³ and the ring can beeither a single or double bond, as indicated by the dashed line. Incertain embodiments, the bond must be double bond, e.g., when R³ is ═NH.In other instances, the bond must be a single bond, e.g., when R³ is H.

In a further embodiment within this seventh subclass, the presentinvention is directed to a method of enhancing a sweet taste, saidmethod comprising utilizing a compound of Formula XVI:

wherein R¹ is H or C₁₋₆ alkyl; R² is H; R³¹ is optionally substitutedphenyl, preferably optionally substituted by one or more of C₁₋₆ alkyl,C₁₋₆ alkoxy, halogen, hydroxyl, or nitro; and n is 0 to 3. In oneexample within this embodiment, R¹ is hydrogen. In another, n is 1. Inanother, R³¹ is phenyl substituted by a nitro group, and preferably R³¹is 3-nitrophenyl.

In an eighth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XVIII:

wherein R¹ is H or C₁₋₆ alkyl;

R² is H, C₁₋₆ alkyl, or optionally substituted phenyl, preferablyoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, and nitro; and

R³ is NH—C(═O)—(CH₂)_(n)—R^(a), wherein, n is 0 to 3 and R^(a) isselected from (a) optionally substituted phenyl, preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, andnitro, and (b) NR³¹R³², wherein R³¹ and R³² are independently selectedfrom H or C₁₋₆ alkyl and n is 0 to 3, or R³ is

wherein R³³ is optionally substituted phenyl, preferably optionallysubstituted by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, or nitro; R³⁴ is H or C₁₋₆ alkyl; and m is 0 to 3.

In one embodiment within this eighth subclass, R² is phenyl substitutedby a halogen, preferably chlorine. In another embodiment, R² is4-chlorophenyl. In another, R² is C₁₋₆ alkyl, preferably methyl.

In a further embodiment within the eighth subclass, the presentinvention is directed to a method of enhancing a sweet taste, saidmethod comprising utilizing a compound of Formula XIX:

wherein R¹ is H or C₁₋₆ alkyl;

R² is H or C₁₋₆ alkyl;

R³³ is optionally substituted phenyl, preferably optionally substitutedby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, or nitro;

R³⁴ is H or C₁₋₆ alkyl; and

m is 0 to 3.

In one embodiment within this eighth subclass, R¹ is hydrogen. Inanother embodiment, R² is C₁₋₆ alkyl, preferably methyl. In another, R³⁴is an isopropyl group. In another, R³³ is phenyl.

In a further embodiment within the eighth subclass, the presentinvention is directed to a method of enhancing a sweet taste, saidmethod comprising utilizing a compound of Formula XIX wherein:

R¹ is H or C₁₋₆ alkyl;

R² is H or C₁₋₆ alkyl;

R³³ is optionally substituted phenyl, preferably optionally substitutedby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, or nitro;

R³⁴ is H or C₁₋₆ alkyl; and

m is 1.

In one example within this embodiment, R¹ is hydrogen. In anotherexample, R² is C₁₋₆ alkyl, preferably methyl. In one, R³⁴ is anisopropyl group. In another, R³³ is phenyl.

In further embodiment within the eighth subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XX:

wherein:

R¹ is H, C₁₋₆ alkyl, or optionally substituted phenyl, preferablyoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, and nitro;

R² is H, C₁₋₆ alkyl, or optionally substituted phenyl, preferablyoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, and nitro;

R³¹ is either an optionally substituted phenyl, preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, andnitro, or is NR^(5a)R^(6a), wherein R^(5a) and R^(6a) are independentlyselected from H or C₁₋₆ alkyl; and

n is 0 to 3.

In further embodiment within the eighth subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XX wherein R¹ is hydrogen orC₁₋₆ alkyl; R² is an optionally substituted phenyl, preferablyoptionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, hydroxyl, or nitro; R³¹ is NR^(5a)R^(6a); and n is 0 to 3. In afurther embodiment, R² is substituted by a halogen, preferably chlorine.In another embodiment, R² is 3-chlorophenyl. In another embodiment, R¹is hydrogen. In another embodiment, R^(5a) and R^(6a) are both alkylgroups, preferably methyl.

In further embodiment within the eighth subclass, the present inventionis directed to a method of enhancing a sweet taste, said methodcomprising utilizing a compound of Formula XX wherein R¹ is hydrogen orC₁₋₆ alkyl; R² is H, C₁₋₆ alkyl, optionally substituted phenyl,preferably optionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, hydroxyl, or nitro; n is 0 to 3; R³¹ is optionallysubstituted phenyl, preferably optionally substituted by one or more ofC₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, or nitro; and n is 0 to 3.In one embodiment, R² is an optionally substituted phenyl, preferably R²is substituted by one or more alkyl groups. In a further embodiment, R²is a ethyl-substituted phenyl, preferably 3-ethylphenyl. In oneembodiment, R³ is substituted by one or more methyl groups, preferablyR³¹ is 3,5-dimethyoxyphenyl. In one embodiment, n is zero.

In a ninth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XXI:

wherein R³ is optionally substituted phenyl, preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, andnitro; R⁴ is H; and R^(a) is H or C₁₋₆ alkyl. In an embodiment of thisninth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XXI wherein R^(a) is H or C₁₋₆ alkyl; and R³ is a disubstitutedphenyl containing C₁₋₆ alkyl, halogen, or NO₂, or preferably is adisubstituted phenyl containing a C₁₋₆ alkoxy substituent and a halogensubstituent.

In a further embodiment of the ninth subclass, the present invention isdirected to a method of enhancing a sweet taste, said method comprisingutilizing a compound of Formula XXI wherein R^(a) is H or C₁₋₆ alkyl;and R³ optionally substituted phenyl, preferably optionally substitutedby one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, or nitro.In one embodiment, R³ is a phenyl substituted with a halogen and a C₁₋₆alkyloxy group, preferably R³ is 2-methoxy-3-chlorophenyl.

In a tenth subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XXII wherein:

wherein R³ is H or C₁₋₆ alkyl; R^(a) is H or C₁₋₆ alkyl; and R⁴ isoptionally substituted phenyl, preferably optionally substituted by oneor more substituents independently selected from the group consisting ofC₁₋₆ alkyl, halogen, and nitro. In an embodiment of this tenth subclass,the present invention is directed to a method of enhancing a sweettaste, said method comprising utilizing a compound of Formula XXIIwherein R³ is H or C₁₋₆ alkyl; R⁴ is phenyl; and R^(a) is H or C₁₋₆alkyl.

In a eleventh subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XXIII:

wherein R¹ is H, C₁₋₆ alkyl, or halogen;

R² is H or C₁₋₆ alkyl;

R³ is H, halogen, C₁₋₆ haloalkyl, preferably trifluoromethyl, or C₁₋₆alkyl;

R⁵ is phenylamide (i.e., C(O)NH-Ph) optionally substituted with one ormore substituents selected from the group consisting of H, halogen, C₁₋₆haloalkyl, preferably trifluoromethyl, nitro, C₁₋₆ alkyl, and C₁₋₆alkyloxy.

In one embodiment within this eleventh subclass, the invention comprisesthe use of a compound of the following formula:

wherein R¹, R², and R³ are defined as above. In another embodiment ofthis eleventh subclass, the present invention is directed to a method ofenhancing a sweet taste, said method comprising utilizing a compound ofFormula XXIII wherein R¹ is halogen; R² is H or C₁₋₆ alkyl; R³ is C₁₋₆haloalkyl, preferably CF₃; and the phenylamide group is substituted withone or two groups independently selected from the group consisting ofhalogen, C₁₋₆ haloalkyl, NO₂, C₁₋₆ alkyl, and C₁₋₆ alkyloxy.

In certain embodiments of this eleventh subclass, R¹ is halogen and R³is CF₃.

Examples of suitable compounds for use in the method of the presentinvention include: ethyl2-(3-methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate;

-   2-(2-(2-methoxyphenoxy)ethylthio)-1H-benzo[d ]imidazole;-   methyl 3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate;-   6-(4-chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole;-   6-p-tolylimidazo[2,1-b][1,3,4]thiadiazole;-   N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide;-   2-(2-(2-(2,6-dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol;-   1-ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole;-   2,4-diphenyl-5,5-dimethylimidazole-1-oxide;-   1-allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea;-   2-(2-iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone;-   3-benzyl-1-isopropyl-5-(4-methylthiazol-2-yl)pyrimidine-2,4(1H,3H)-dione;-   2-(3-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine;-   N-(4-(4-ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide;-   1-phenylthiochromeno[4,3-d]imidazol-4(1H)-one;-   N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;-   5-chloro-1-methyl-3-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxamide;    and physiologically acceptable salts thereof.

Further examples of suitable compounds for use in the method of thepresent invention include:N-(4-(((2,6-dimethoxypyrimidin-4-yl)amino)sulfonyl)phenyl)-4-nitrobenzamide;

-   4-phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one;-   5-(perfluorophenoxy)isophthalic acid;-   2-(dibenzylamino)acetic acid;-   ethyl 2-cyano-2-(phenyldiazenyl)acetate; and

physiologically acceptable salts thereof.

The methods of the present invention also include the use of aphysiologically acceptable salt of a compound according to Formula I.The term physiologically acceptable salt refers to an acid- and/orbase-addition salt of a compound according to Formula I. Acid-additionsalts can be formed by adding an appropriate acid to the compoundaccording to Formula I. Base-addition salts can be formed by adding anappropriate base to the compound according to Formula I. Said acid orbase does not substantially degrade, decompose, or destroy said compoundaccording to Formula I. Examples of suitable physiologically acceptablesalts include hydrochloride, hydrobromide, acetate, furmate, maleate,oxalate, and succinate salts. Other suitable salts include sodium,potassium, carbonate, and tromethamine salts.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of Formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

The compounds of the present invention can have asymmetric centers atcertain of the nitrogen or sulfur atoms. Consequently, these isomers ormixtures thereof are part of the present invention.

The compounds of the present invention may also display other instancesof chirality, such as atropoisomerism. Thus, these isomers or mixturesthereof are part of the invention. It is further understood that thepresent invention encompasses the use of tautomers of a compound ofFormula I. Tautomers are well-known in the art and include keto-enoltautomers.

The compounds of the present invention may also contain varying amountsof isotopes of carbon, hydrogen, nitrogen, oxygen, sulfur, halogen,etc.; such as ¹³C, ¹⁴C, deuterium, tritium, ¹⁵N, ¹⁸O, ¹²⁸I, etc. Some ofthe isotopic content is naturally occurring, but the compounds of thepresent invention may be enriched or depleted in one or more of these.Thus, these isotopes or mixtures thereof are part of the invention.

The compounds of Formula I may also be solvated, including hydrated.Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

Certain compounds within the scope of Formula I may be derivativesreferred to as “prodrugs.” The expression “prodrug” denotes a derivativeof a known direct acting agent, wherein the derivative has therapeuticvalue that may be similar to, greater than, or less than that of theagent. Generally, the prodrug is transformed into the active agent by anenzymatic or chemical process when delivered to the subject, cell, ortest media. In certain instances, prodrugs are derivatives of thecompounds of the invention which have metabolically cleavable groups andbecome by solvolysis or under physiological conditions the compounds ofthe invention which are pharmaceutically active in vivo. For example,ester derivatives of compounds of this invention are often active invivo, but not in vitro. Other derivatives of the compounds of thisinvention have activity in both their acid and acid derivative forms,but the acid derivative form often offers advantages of solubility,tissue compatibility, or delayed release in the mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacid with a suitable alcohol, or amides prepared by reaction of theparent acid compound with an amine. Simple aliphatic or aromatic estersderived from acidic groups pendent on the compounds of this inventionare preferred prodrugs.

When any variable occurs more than one time in any constituent or inFormula I, its definition on each occurrence is independent of itsdefinition at every other occurrence, unless otherwise indicated. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The term “alkyl,” as used herein by itself or as part of another group,refers to both straight and branched chain radicals of up to 10 carbons,unless the chain length is limited thereto, such as methyl, ethyl,propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl,1-methylbutyl, isobutyl, pentyl, t-amyl (CH₃CH₂(CH₃)₂C—), hexyl,isohexyl, heptyl, octyl, or decyl.

The term “alkenyl,” as used herein by itself or as part of anothergroup, refers to a straight or branched chain radical of 2-10 carbonatoms, unless the chain length is limited thereto, including, but notlimited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, pentenyl, 1-hexenyl, and 2-hexenyl.

The term “alkylene,” as used herein by itself or as a part of anothergroup, refers to a diradical of an unbranched saturated hydrocarbonchain, having, unless otherwise indicated, from 1 to 15 carbon atoms,preferably 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms.This term is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene, and the like.

The term “alkenylene,” as used herein by itself or part of anothergroup, refers to a diradical of an unbranched, unsaturated hydrocarbonchain, having, unless otherwise indicated, from 2 to 15 carbon atoms,preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms,and having at least 1 and preferably from 1 to 6 sites of vinylunsaturation. This term is exemplified by groups such as ethenylene(—CH═CH—), propenylene (—CH₂CH═CH—, —CH═CHCH₂—), and the like.

The term “alkoxy,” as used herein by itself or as part of another group,refers to any of the above alkyl groups linked to an oxygen atom.Typical examples are methoxy, ethoxy, isopropyloxy, sec-butyloxy, andt-butyloxy.

The term “alkenyloxy,” as used herein by itself or as part of anothergroup, refers to any of the above alkenyl groups linked to an oxygenatom. Typical examples include ethenyloxy, propenyloxy, butenyloxy,pentenyloxy, and hexenyloxy.

The term “aryl,” as used herein by itself or as part of another group,refers to monocyclic or bicyclic aromatic groups containing from 6 to 14carbons in the ring portion, preferably 6-10 carbons in the ringportion. Typical examples include phenyl, naphthyl, anthracenyl, orfluorenyl.

The term “heteroaryl,” as used herein by itself or as part of anothergroup, refers to groups having 5 to 14 ring atoms; 6, 10, or 14 πelectrons shared in a cyclic array; and containing carbon atoms and 1,2, 3, or 4 oxygen, nitrogen, or sulfur atoms. Examples of heteroarylgroups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl,thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl,xanthenyl, phenoxathinyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,pteridinyl, 4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, and tetrazolylgroups. Further heteroaryls are described in A. R. Katritzky and C. W.Rees, eds., Comprehensive Heterocyclic Chemistry: The Structure,Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8,Pergamon Press, NY (1984).

The term “halogen” or “halo,” as used herein by itself or as part ofanother group, refers to chlorine, bromine, fluorine or iodine.

The term “monoalkylamine” or “monoalkylamino,” as used herein by itselfor as part of another group, refers to the group NH₂ wherein onehydrogen has been replaced by an alkyl group, as defined above.

The term “dialkylamine” or “dialkylamino,” as used herein by itself oras part of another group refers to the group, NH₂ wherein both hydrogenshave been replaced by alkyl groups, as defined above.

The term “hydroxyalkyl,” as used herein by itself or as part of anothergroup, refers to any of the above alkyl groups wherein one or morehydrogens thereof are substituted by one or more hydroxyl moieties.

The term “haloalkyl,” as used herein by itself or as part of anothergroup, refers to any of the above alkyl groups wherein one or morehydrogens thereof are substituted by one or more halo moieties. Typicalexamples include fluoromethyl, trifluoromethyl, trichloroethyl, andtrifluoroethyl.

The term “carboxyalkyl,” as used herein by itself or as part of anothergroup, refers to any of the above alkyl groups wherein one or morehydrogens thereof are substituted by one or more carboxylic acidmoieties.

The term “heteroatom” is used herein to mean an oxygen atom (“O”), asulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized thatwhen the heteroatom is nitrogen, it may form an NR^(a)R^(b) moiety,wherein R^(a) and R^(b) are, independently from one another, hydrogen oralkyl, or together with the nitrogen to which they are bound, form asaturated or unsaturated 5-, 6-, or 7-membered ring.

The term “oxy” means an oxygen (O) atom.

The term “thio” means a sulfur (S) atom.

As used herein, unless otherwise indicated, Cy represents a cyclo groupfused to another ring in the chemical structure of which the Cy is apart. Suitable cyclo groups include cycloalkyl, cycloheteroalkyl, aryl,and heteroaryl. The cyclo group can be a monocyclic group or polycyclicgroup, such as a bicyclic group. Thus, if the Cy group is a bicyclicring system, the entire molecule will comprise a tricyclic ring systemincluding the core ring show in Formula I. The cyclo group may contain5-10 carbon atoms and/or heteroatoms as part of its ring, excluding theshared ring atoms of the other ring system. Suitable cyclo groupsinclude any aryl and heteroaryl rings described herein.

For instance, in the following structure,

Cy represents a cyclo group fused to the five-memberednitrogen-containing heterocycle. Thus, the above structure covers, amongother possibilities, a benzimidazole compound. Further, and by way ofexample, a Cy containing 5-10, preferably 5-7, carbon atoms and/orheteroatoms in the above structure would indicate that the Cy groupcontains 5-10, preferably 5-7, carbon atoms and/or heteroatoms includingthe 2 carbon atoms shared between the cyclo ring and the imidazole ring.

Generally and unless defined otherwise, the phrase ‘optionallysubstituted’ used herein refers to a group or groups being optionallysubstituted with one or more substituents independently selected fromthe group consisting of: halogen, nitro, cyano, OR₂₂, alkyl which may besubstituted with one or more occurrences of R₂₃, alkenyl which may besubstituted with one or more occurrences of R₂₃, alkynyl which may besubstituted with one or more occurrences of R₂₃, cycloalkyl which may besubstituted with one or more occurrences of R₂₃, aryl which may besubstituted with one or more occurrences of R₂₃, heterocyclo which maybe substituted with one or more occurrences of R₂₃, SR₂₂, SO₂R₂₂,COOR₂₂, C(O)R₂₂, CONR₂₄R₂₅, SO₂NR₂₄R₂₅, SO₂N(H)C(O)R₂₂, SO₂N(H)CO₂R₂₂wherein R₂₂ is not H, NR₂₄R₂₅, N(R₂₄)SO₂R₂₅, N(R₂₄)C(O)_(m)R₂₅ (whereinm is 1 or 2), N(R₂₄)C(O)NR₂₅R₂₆, N(R₂₄)SO₂NR₂₅R₂₆, OC(O)R₂₂, OC(O)OR₂₂,OC(O)NR₂₅R₂₆, C(O)N(H)SO₂NR₂₅R₂₆, C(O)N(H)SO₂R₂₅, oxo (or keto, i.e.,═O), thioxo (i.e., ═S), imino (i.e., ═NR₂₇), NR₂₇—C(═NR₂₈)R₂₉,NR₂₇—C(═NR₂₈)NR₂₉R₃₀, C(═NR₂₇)NR₂₈R₂₉, OC(═NR₂₇)NR₂₈R₂₉, OC(═NR₂₇)R₂₈,C(═NR₂₇)R₂₈, and C(═NR₂₇)OR₂₂; wherein R₂₂ is selected from H, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, orC₁-C₉ heterocyclo each of which may be substituted with 1 to 3independent occurrences of R₂₃; wherein R₂₄, R₂₅, and R₂₆ are selectedfrom C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, or C₁-C₉ heterocyclo each of which may be substituted with 1 to 3independent occurrences of R₂₃; or R₂₄ and R₂₅, or R₂₄ and R₂₆, or R₂₅and R₂₆ may be joined by an alkylene or an alkenylene chain to form a 5-to 8-membered heterocyclo ring which is defined as for heterocyclowherein the substituents may be one or more occurrences of R₂₃; whereinR₂₇, R₂₈, R₂₉, and R₃₀ are independently selected from the groupconsisting of H, nitro, cyano, OH, O(C₁-C₆ alkyl), C(O)R₂₂, C(O)NR₂₄R₂₅,CO₂R₂₂ (with the proviso that R₂₂ is not H), SO₂R₂₂, SO₂NR₂₄R₂₅, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, andC₁-C₉ heterocyclo; or R₂₇ and R₂₈, or R₂₇ and R₂₉, or R₂₇ and R₃₀, orR₂₈ and R₂₉, or R₂₈ and R₃₀, or R₂₉ and R₃₀ are joined by an alkylene oralkenylene chain to form a 5-8 membered ring that may be optionallysubstituted with one or more occurrences of R₂₃; wherein each occurrenceof R₂₃ is independently selected from the group consisting of halogen,nitro, cyano, OR₃₁, alkyl optionally substituted with halogen,cycloalkyl optionally substituted with halogen, aryl optionallysubstituted with halogen, hydroxy, nitro, methoxy, trifluoromethyl,cyano, carbomethoxy, CONH₂, or CHO, heterocyclo optionally substitutedwith halogen, hydroxy, nitro, methoxy, trifluoromethyl, cyano,carbomethoxy, CONH₂, or CHO, SR₃₁, CO₂R₃₁, C(O)R₃₁, CONR₃₂R₃₃,SO₂NR₃₂R₃₃, NR₃₂R₃₃, N(R₃₂)SO₂R₃₃, N(R₃₂)C(O)_(m)R₃₃ (m is 1 or 2),N(R₃₂)C(O)NR₃₃R₃₄, N(R₃₂)SO₂NR₃₃R₃₄, OC(O)R₃₁, OC(O)OR₃₁, SO₂R₃₁,SO₂N(H)C(O)R₃₁, SO₂N(H)CO₂R₃₁ wherein R₃₁ is not H, C(O)N(H)SO₂NR₃₂R₃₃,C(O)N(H)SO₂R₃₁, OC(O)NR₃₂R₃₃, NR₃₅—C(═NR₃₆)R₃₇, NR₃₅—C(═NR₃₆)OR₃₁,NR₃₅—C(═NR₃₆)NR₃₇R₃₈, C(═NR₃₅)NR₃₆R₃₇, OC(═NR₃₅)R₃₆, OC(═NR₃₅)NR₃₆R₃₇,and C(═NR₃₅)OR₃₁, R₃₁ is selected from unsubstituted alkyl, alkenyl,unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted aryl, andunsubstituted heterocyclo; wherein each occurrence of R₃₂, R₃₃ and R₃₄is independently selected from the group consisting of unsubstitutedalkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstitutedcycloalkyl, unsubstituted aryl, unsubstituted heterocyclo; or R₃₂ andR₃₃, or R₃₂ and R₃₄, or R₃₃ and R₃₄, are joined by an unsubstitutedalkylene or unsubstituted alkenylene chain to form a 5-8 memberedunsubstituted heterocyclo ring; and wherein R₃₅, R₃₆, R₃₇, are R₃₈independently selected from the group consisting of nitro, cyano,unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl,unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heterocyclo;or R₃₅ and R₃₆, or R₃₅ and R₃₇, or R₃₅ and R₃₈, or R₃₆ and R₃₇, or R₃₆and R₃₈, or R₃₇ and R₃₈ is joined by an unsubstituted alkylene chain orunsubstituted alkenylene chain to form a 5- to 8-membered unsubstitutedheterocyclo ring.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl.”Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

In a subgroup of the invention, the phrase “optionally substituted”refers to a group or groups being optionally substituted with one ormore substituents independently selected from the group consisting ofamino, hydroxyl, nitro, halogen, cyano, thiol, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₆ cycloheteralkyl,C₃₋₆ cycloheteroalkenyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₁₋₆alkoxy, C₃₋₆ alkenyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylenedioxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₆₋₁₀ aryl(C₁₋₆)alkyl, C₆₋₁₀ aryl(C₂₋₆)alkenyl, C₆₋₁₀aryl(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl, C₁₋₆ aminoalkoxy, C₁₋₆ hydroxyalkyl,C₂₋₆ hydroxyalkoxy, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl,carboxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono(C₁₋₄)alkylamino(C₂₋₆)alkoxy,di(C₁₋₄)alkylamino(C₂₋₆)alkoxy C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀carboxyalkyl)amino, aminocarbonyl, C₆₋₁₄ aryl(C₁₋₆)alkoxycarbonyl, C₂₋₆alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkynylsulfonyl, C₆₋₁₀arylsulfonyl, C₆₋₁₀ aryl(C₁₋₆)alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonamido, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ aryl(C₁₋₆)alkylsulfonamido, C₁₋₆ alkyliminoamino, formyliminoamino, C₂₋₆carboxyalkoxy, C₂₋₆ carboxyalkyl, and carboxy(C₁₋₆)alkylamino.

A “tastant” is any substance capable of eliciting gustatory excitation,i.e., stimulation the sense of taste. When a subject ingests a tastant,and that tastant encounters a taste receptor cell in the appropriateconcentration, an action potential is produced which, via synapses withprimary sensory neurons, communicates the signal registered by thereceptor, via afferent nerves, to the appropriate region of the sensorycortex of the brain, resulting in the perception of a particular tasteby the subject. Examples of sweet tastants include, but are not limitedto, sugar, (sucrose), dextrose, maltose, dextrin, dried invert sugar,fructose, levulose, lactose, galactose, corn syrup, malodextrin, honey,sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, malitol,hydrogenated starch hydrolysates, maltitol and the like, thaumatin,aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl maltol,glycine, isomalt, spray dried licorice root, glycyrrhizin, sodiumgluconate, glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®,EQUAL®, SWEET 'N LOW®, and NUTRASWEET®.

The phrase “a sweet tastant” as used herein means “one or more sweettastants.” Thus, the methods of this invention may compriseadministering one sweet tastant or multiple sweet tastants and thecompositions of this invention may comprise one sweet tastant ormultiple sweet tastants. For example, the food products of thisinvention can comprise both sucrose and corn syrup as sweet tastants, orsucrose and aspartame as sweet tastants, or saccharin and sucralose assweet tastants. In some cases a sweet tastant(s) may be present at asuboptimal amount where its sweetness is enhanced or intensified by useof this invention.

Although detailed definitions have not been provided for every term usedabove, each term is understood by one of ordinary skill in the art.

As explained above, the present invention provides methods, compounds,and compositions that are useful, for example, for enhancing sweettastes. The methods of the present invention enable one to use a knownsweetening agents, or sweet tastants, in a reduced amount combined witha compound according to Formula I, or any of the specific subgroups orspecific compounds described herein, in order to achieve the same levelof sweetness when the known sweet tastant is used alone in thetraditional amount. By way of brief example, a common carbonated colabeverage may contain about 20 to 30 grams of sugar (e.g., fructose) andabout 100 calories per 8 ounce serving. The present invention enablesone to prepare a similar cola beverage with substantially reduced sugarand caloric content but with the same level of sweetness. The compoundsidentified in here, e.g., according to Formula I, enhance the sweettaste produced by the reduce sugar content, thereby creating an enhancedsweet taste based on the reduced level of sweet tastant, e.g., tablesugar.

As mentioned above, the above described compounds may be used to enhancea sweet taste. Such enhancement may be in vitro or in vivo. The amountof the compound of Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, used to enhance thesweet taste may not necessarily be the same when used in vivo comparedto in vitro. Factors such as pharmacokinetics and pharmacodynamics ofthe particular compound may require that a larger or smaller amount ofthe compound of Formula I, or any of the specific subgroups, subclasses,or specific compounds described above, be used when enhancing a tastemodulating protein in vivo. Accordingly, one aspect of the presentinvention is a method of enhancing a sweet taste by utilizing a compoundaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above.

The compounds of the present invention can be used to enhance the sweettaste of a food product exhibiting a sweet taste comprisingadministering to a subject a food product comprising a sweet tastant andone or more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above.Furthermore, in a preferred embodiment, the food product comprises acompound of Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above in an amount sufficient to enhancethe sweet taste.

The compounds of this invention may be used to enhance the desirableproperties of sweetness in any food product. The phrase “food product”as used herein includes but is not limited to fruits, vegetables,juices, meat products such as ham, bacon and sausage; egg products,fruit concentrates, gelatins and gelatin-like products such as jams,jellies, preserves, and the like; milk products such as ice cream, sourcream and sherbet; icings, syrups including molasses; corn, wheat, rye,soybean, oat, rice and barley products, nut meats and nut products,cakes, cookies, confectionaries such as candies, gums, fruit flavoreddrops, and chocolates, chewing gum, mints, creams, icing, ice cream,pies and breads, beverages such as coffee, tea, carbonated soft drinks,such as COKE® and PEPSI®, non-carbonated soft drinks, juices and otherfruit drinks, sports drinks such as GATORADE®, coffee, teas, iced teas,coca, alcoholic beverages, such as beers, wines and liquors, andKOOL-AID.® Preferably, the food products in which the sweetness isenhanced with the compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,will contain a decreased level of known sweet tastant(s). For example,an improved carbonated soft drink can be produced with the samesweetness as the known carbonated soft drink but with a lower sugarcontent by adding a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above.In some cases a sweet tastant(s) may be present at a suboptimal amountwhere its sweetness is enhanced or intensified by use of this invention.

Food products also include condiments such as herbs, spices andseasonings, flavor enhancers such as monosodium glutamate. A foodproduct also includes prepared packaged products such as dieteticsweeteners, liquid sweeteners, granulated flavor mixes which uponreconstitution with water provide non-carbonated drinks, instant puddingmixes, instant coffee and tea, coffee whiteners, malted milk mixes, petfoods, livestock feed, tobacco and materials for baking applicationssuch as powdered baking mixes for the preparation of breads, cookies,cakes, pancakes, donuts and the like. Food products also includesugar-free foods or beverages designed for diabetics and others thatcannot consume products containing sucrose and diet or low-calorie foodand beverages containing little or no sucrose. Especially preferred foodproducts are carbonated beverages containing one or more of the subjectenhancers. Other examples of food products envisioned in accordance withthe present invention are described below and throughout thespecification.

In one embodiment, the present invention is directed to a method ofenhancing the sweet taste of a food product comprising a administeringto a subject a food product comprising a sweet tastant and one or morecompounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above. Furthermore, in apreferred embodiment, the food product comprises a compound of FormulaI, or any of the specific subgroups, subclasses, or specific compoundsdescribed above in an amount sufficient to enhance the sweet taste.Specific sweet tastants to which one of more compounds of Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above, can be added to enhance its sweet taste include but arenot necessarily limited to sugar, (sucrose), dextrose, maltose, dextrin,dried invert sugar, fructose, levulose, lactose, galactose, corn syrup,malodextrin, honey, sugar alcohols such as sorbitol, mannitol, xylitol,lactitol, malitol, hydrogenated starch hydrolysates, maltitol and thelike, thaumatin, aspartame, acesulfame K, saccharin, sucralose,glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones, zincgluconate, ethyl maltol, glycine, isomalt, spray dried licorice root,glycyrrhizin, sodium gluconate, glucono-delta-lactone, ethyl vanillin,vanillin, SPLENDA®, EQUAL®, SWEET 'N LOW®, and NUTRASWEET®. Specificfood products in which an enchanted sweet taste is desired include butare not limited to cakes, cookies, confectionaries such as candies, gumsand chocolates, creams, icing, ice cream, pies and breads. Specific foodproducts which are beverages include soft drinks such as COKE®, andPEPSI®, juices and other fruit drinks, sports drinks such as GATORADE®,coffee, teas, iced teas, coca, alcoholic beverages and KOOL-AID®. In oneembodiment, the food product comprises one sweet tastant. In anotherembodiment, the food product comprises more than one sweet tastant. Incertain embodiments, the food product comprises sucrose and corn syrup;sucrose and aspartame; or saccharin and sucralose as sweet tastants.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a food product selected from fruits,vegetables, juices, meat products such as ham, bacon and sausage; eggproducts, fruit concentrates, gelatins and gelatin-like products such asjams, jellies, preserves, and the like; milk products such as ice cream,sour cream and sherbet; icings, syrups including molasses; corn, wheat,rye, soybean, oat, rice and barley products, nut meats and nut products,cakes, cookies, confectionaries such as candies, gums, fruit flavoreddrops, and chocolates, creams, icing, ice cream, pies and breads,comprising administering to a subject a sweet tastant and a compound ofFormula I.

In a preferred embodiment, the invention is directed to a method ofdecreasing the amount of sweet tastant, such as sucrose, fructose, orsucralose, needed in a consumable product, such as a food product orpharmaceutical product, to exhibit a given level of sweetness.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a food product comprising administering toa subject a sweetener and one or more compounds according to Formula I.Sweeteners are well known in the art, and include compounds such assugar, (sucrose), dextrose, maltose, dextrin, dried invert sugar,fructose, levulose, lactose, galactose, corn syrup, malodextrin, honey,sugar alcohols such as sorbitol, mannitol, xylitol, lactitol, malitol,hydrogenated starch hydrolysates, maltitol and the like, thaumatin,aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl maltol,glycine, isomalt, spray dried licorice root, glycyrrhizin, sodiumgluconate, glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®,EQUAL®, SWEET 'N LOW®, and NUTRASWEET®. Especially useful are the blendsof the compounds of Formula I of this invention and saccharin orphysiologically acceptable salts thereof. Examples of saccharin saltsinclude the sodium, potassium, calcium and ammonium salts. In blendswith saccharin, the compounds of this invention may reduce or completelymask the recognized undesirable bitter aftertaste of the saccharin.

Any of the food products described herein may comprise one or more sweettastants. In one embodiment, the food products comprise one sweettastant. In a further embodiment, the food product comprises more thanone sweet tastant. In certain embodiments, the food product comprisessucrose and corn syrup as sweet tastants, or sucrose and aspartame, orsaccharin and sucralose.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the food product.

In each of the embodiments of the methods described herein, a compoundof Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used in varying ratios to the tastant,i.e. the agent that is believed to cause the sweet taste. For example, acomposition of the invention may comprise a compound of Formula I in amolar ratio of about 1:10⁶ to about 10:1, or alternatively administeredin a molar ratio of about 1:10⁵, about 1:10⁴, about 10:10³, about 1:10²,relative to the tastant. As will be appreciated, the various ranges andamounts of the compound of Formula I can be used, with modifications ifpreferred, in each of the embodiments described herein. The compositionmay also comprise 10⁻⁴% to 10⁻¹% of the compound of Formula I relativeto the sweet tastant, by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the food product in an amount ranging from about 0.001 mg toabout 10 g per serving, preferably about 0.01 mg to about 5 g perserving, or alternatively, from 0.05 mg to about 1 g per serving. Thepresent invention also contemplates food products with amounts of thecompound of Formula I of about 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 500 mg, 1 g, 2 g, 5 g and 8 g per serving.

The method may be performed such that the sweet taste of the foodproduct or food ingredient being enhanced by the compound of Formula Iis enhanced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, or 95%, or from about 60% to about 99%, or alternatively from about20% to about 50%. Thus, in a more specific embodiment, the methodcomprises administering a food product or food ingredient comprising asweet tastant and one or more compounds according to Formula I, whereinthe one or more compounds according to Formula I are present in anamount sufficient to enhance a sweet taste, produced by the foodproduct, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 95%, or from about 60% to about 99%, or alternatively from about 30%to about 70%. Of course, in other embodiments, the sweetness may beenhanced to differing extents.

Any amount of the compound of Formula I that provides the desired degreeof sweetness enhancement can be used. For example, a compound of FormulaI may be used at a concentration of about 30 μg/L to about 1.5 g/L toenhance a sweet taste. Alternatively, concentrations of about 0.1 to 100mg/L of a compound of Formula I may be used to enhance a sweet taste. Itis contemplated that between 0.1 mg/L and 100 mg/L of the compound ofFormula I is present and between 10 g/L and 100 g/L of sweet tastant ispresent. For example, a composition could contain 0.1 mg/L, 1 mg/L, or10/L mg of the compound of Formula I for 10 mg/L of the tastant.Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50 mg/Lof the compound of Formula I for 50 mg/L of the tastant. In otherembodiments, the composition contains 1 mg/L, 10 mg/L or 100 mg/L of thecompound of Formula I for 100 g/L of the tastant.

In one embodiment, the present invention is directed to a method ofenhancing the sweet taste of a food product selected from a beverage ordrink comprising administering to a subject a beverage or drinkcomprising a sweet tastant and one or more compounds according toFormula I. Examples of suitable beverages in which having a sweet tasteis desired include, but are not limited to coffee, teas, such as blacktea, green tea, fermented tea, semi-fermented tea, carbonated softdrinks, such as COKE® and PEPSI®, non-carbonated soft drinks, lemonade,juices and other fruit drinks, sports drinks, such as GATORADE®, icedteas, coca, alcoholic beverages, such as beers, wines and liquors, andKOOL-AID.® In certain embodiments, the sweetness enhancing amount of acompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, has a range of fromabout 0.01 milligrams to about 5.0 grams per 100 mL. In otherembodiments, the sweetness enhancing effective amount of a compoundaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, has a range of from about 0.1 mg toabout 2 grams per 1 L. Alternatively, a compound according to Formula I,or any of the specific subgroups, subclasses, or specific compoundsdescribed above, is administered in an amount of about 1 gram per 100mL. In one embodiment, the beverage or drink comprises one sweettastant. In another embodiment, it comprises more than one sweettastant. In certain embodiments, the beverage or drink comprises sucroseand corn syrup, or it comprises sucrose and aspartame, or it comprisessaccharin and sucralose as sweet tastants.

One embodiment of the invention is directed to a method of enhancing thesweet taste of a cola beverage, such as COKE® or PEPSI® comprisingadministering to a subject a cola drink comprising a sweet tastant andone or more compounds according to Formula I. In a preferred embodiment,the cola beverage will contain a reduced amount of sugar but maintainsubstantially the original level of sweet taste.

Cola beverages are prepared by mixing cola concentrate with carbonatedwater. Typically about 50 mL of cola concentrate is added per 250 mL ofcarbonated water. Cola concentrate can be prepared by mixing colaflavor, caramel color, and optionally caffeine with water, one or moresweet tastants, one or more compounds of Formula I, and one or more acidcomponents.

A cola flavor refers to either a natural or artificial flavor. Such colaflavors are commercially available. Commercial cola flavors areavailable, for example, from International Flavor and Fragrances,Dayton, N.J.; Artificial—#13573011 and Natural #K3559549. Commercialcola flavors are also available from Tastemaker, Cincinnati, Ohio, andGivaudan Roure, Clifton, N.J.

The acid component refers to an ingredient that contributes sourness tothe beverage and is added to balance the flavor profile by reducingchemical or sweetener side tastes. Acids may include malic acid, citricacid, phosphoric acid or combinations thereof.

Examples of sweet tastants include but are not limited to the groupconsisting of sugar, (sucrose), dextrose, maltose, dextrin, dried invertsugar, fructose, levulose, lactose, galactose, corn syrup, malodextrin,honey, sugar alcohols such as sorbitol, mannitol, xylitol, lactitol,malitol, hydrogenated starch hydrolysates, maltitol and the like,thaumatin, aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin,alitame, cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethylmaltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,SPLENDA®, EQUAL®, SWEET 'N LOW®, and NUTRASWEET®. Sucrose, saccharin,sucralose, and aspartame are preferred. As discussed supra, thecompositions of the invention can comprise more than one sweet tastant.For example, the food products of this invention can comprise bothsucrose and corn syrup as sweet tastants, or sucrose and aspartame assweet tastants, or saccharin and sucralose as sweet tastants.

For example, the cola concentrate can prepared by mixing phosphoric acid(75% Rhone-Poulenc), citric acid (anhydrous, ADM, Decatur, Ill.),caffeine (Mallinckrodt, Paris, Ky.), caramel Color (DS400, Sethness,Chicago, Ill.), cola Flavor (SN018976, International Flavors andFragrances, Dayton, N.J.), sucrose, one or more compounds of Formula I,and water. The concentrate is blended until all ingredients aredissolved (30-40 minutes) using a magnetic stirring plate. Fiftymilliliters of the concentrate are added to 250 mL of carbonated waterto complete the preparation of the cola beverage. Fifty milliliters ofcola concentrate typically contains from 0.01 to 5 mL of phosphoricacid, preferably about 0.01-1 mL, 0.1 to 100 g of sucrose, preferablyabout 1-10 g, about 1×10⁻⁶ g to 10 g of a compound of Formula I,preferably about 1×10⁻³ g to 1 g, about 0.001 g to 0.1 g of citric acid,preferably about 0.005-0.1 g, 0.001 to 1 g of caffeine, preferably about0.01 to 0.1 g of caffeine, 0.01 to 5 g of caramel flavor, preferablyabout 0.05 to 1 g, 0.001 to about 10 mL of cola flavor, preferably about0.01 to about 2 mL.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the cola beverage.

In each of the embodiments of the methods described herein, a compoundof Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used in varying ratios to the tastant,i.e. the agent that is believed to cause the sweet taste. For example, acomposition of the invention may comprise a compound of Formula I in amolar ratio of about 1:10⁶ to about 10:1, or alternatively administeredin a molar ratio of about 1:10⁵, about 1:10⁴, about 1:10³, about 1:10²,relative to the tastant. As will be appreciated, the various ranges andamounts of the compound of Formula I can be used, with modifications ifpreferred, in each of the embodiments described herein. The compositionmay also comprise 10⁻⁴% to 10⁻¹% of the compound of Formula I relativeto the sweet tastant, by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the cola beverage in an amount ranging from about 0.001 mg toabout 10 g per serving, preferably about 0.01 mg to about 5 g perserving, or alternatively, from 0.05 mg to about 1 g per serving. Thepresent invention also contemplates cola beverages with amounts of thecompound of Formula I of about 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 500 mg, 1 g, 2 g, 5 g and 8 g per serving.

Any amount of the compound of Formula I that provides the desired degreeof sweetness enhancement can be used. For example, a compound of FormulaI may be used at a concentration of about 30 μg/L to about 1.5 g/L toenhance a sweet taste. Alternatively, concentrations of about 0.1 to 100mg/L of a compound of Formula I may be used to enhance a sweet taste. Itis contemplated that between 0.1 mg/L and 100 mg/L of the compound ofFormula I is present and between 10 g/L and 100 g/L of sweet tastant ispresent. For example, a composition could contain 0.1 mg/L, 1 mg/L, or10/L mg of the compound of Formula I for 10 mg/L of the tastant.Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50 mg/Lof the compound of Formula I for 50 mg/L of the tastant. In otherembodiments, the composition contains 1 mg/L, 10 mg/L or 100 mg/L of thecompound of Formula I for 100 g/L of the tastant.

In certain embodiments, the improved food product, such as the colabeverage, e.g., COKE® or PEPSI®, will contain a reduced amount of sugarcompared to the prior art cola beverage. The method may be performedsuch that the amount of sugar required to maintain the desired sweetnessof the cola beverage is reduced by at least about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, oralternatively from about 20% to about 50%. Thus, in a more specificembodiment, the cola beverage comprising a sweet tastant and one or morecompounds according to Formula I, contains one or more compoundsaccording to Formula I in an amount sufficient to reduce the amount ofsugar required to maintain the desired sweetness of the beverage isreduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or fromabout 60% to about 99%, or alternatively from about 30% to about 70%. Ofcourse, in other embodiments, the amount of sugar required may bedecreased to differing extents.

Additionally, the invention is directed to a process of preparing animproved food product, wherein the improvement comprises adding one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, to a food product. Incertain embodiments, the one or more compounds according to Formula I,or any of the specific subgroups, subclasses, or specific compoundsdescribed above, are added to the food product in an amount of about 1%to about 25%, about 1% to about 10%, or about 5%, 10%, or 15%, byweight.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of an animal food product comprisingadministering to a subject an animal food product comprising a sweettastant and one or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above.The one or more compounds are preferably in an amount sufficient toenhance one or more sweet tastes associated with the animal foodproduct. Animal food products are well known in the art, see, e.g., U.S.Pat. No. 6,403,142, and include dog food, cat food, rabbit food, and thelike. The animal food product may also be food products useful forfeeding livestock, such as cattle, bison, pigs, chicken, and the like.In another embodiment, the animal food composition of the presentinvention is a solid hypoallergenic pet food comprising a component thatcontains protein or protein fragments wherein all of said component ispartially hydrolyzed and further comprises one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above. In certain embodiments, the one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, are added to ananimal food product in an amount as described above for food products.

Any of the animal food products described herein comprise one or moresweet tastants and one or more of compounds according to Formula I. Inone embodiment, the animal food products comprises one sweet tastant. Ina further embodiment, the food product comprises more than one sweettastant. In certain embodiments, the food product comprises sucrose andcorn syrup as sweet tastants, or sucrose and aspartame, or saccharin andsucralose. In another embodiment, the animal food product contains asweet tastant selected from sugar (sucrose), dextrose, maltose, dextrin,dried invert sugar, fructose, levulose, lactose, galactose, corn syrup,malodextrin, honey, sugar alcohols such as sorbitol, mannitol, xylitol,lactitol, malitol, hydrogenated starch hydrolysates, maltitol and thelike, thaumatin, aspartame, acesulfame K, saccharin, sucralose,glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones, zincgluconate, ethyl maltol, glycine, isomalt, spray dried licorice root,glycyrrhizin, sodium gluconate, glucono-delta-lactone, ethyl vanillin,vanillin, SPLENDA®, EQUAL®, SWEET 'N L OW®, and NUTRASWEET®.

In another aspect, the present invention is directed to method ofenhancing the sweet taste of a pharmaceutical composition comprisingadministering a subject a pharmaceutical composition comprising a sweettastant and a compound of Formula I, as defined above, including any ofthe specific embodiments, subclasses, or species described above, andone or more pharmaceutically acceptable carriers. Preferred compositionsare pharmaceutical compositions comprising a compound selected from oneor more embodiments listed above, and one or more pharmaceuticallyacceptable excipients. Pharmaceutical compositions that comprise one ormore compounds of Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, may be used toformulate pharmaceutical drugs containing one or more active agents thatexert a biological effect other than sweetness enhancement.

The pharmaceutical composition preferably further comprises one or moreactive agents that exert a biological effect. Such active agentsincludes pharmaceutical and biological agents that have an activityother than taste enhancement. Such active agents are well known in theart. See, e.g., The Physician's Desk Reference. Such compositions can beprepared according to procedures known in the art, for example, asdescribed in Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa., USA. In one embodiment, such an active agent includesbronchodilators, anorexiants, antihistamines, nutritional supplements,laxatives, analgesics, anesthetics, antacids, H₂-receptor antagonists,anticholinergics, antidiarrheals, demulcents, antitussives,antinauseants, antimicrobials, antibacterials, antifungals, antivirals,expectorants, anti-inflammatory agents, antipyretics, and mixturesthereof.

In another embodiment, the method of enhancing the sweet taste of apharmaceutical composition comprises administering a pharmaceuticalcomposition containing an active agent is selected from the groupconsisting of antipyretics and analgesics, e.g., ibuprofen,acetaminophen, or aspirin; laxatives, e.g., phenolphthalein dioctylsodium sulfosuccinate; appetite depressants, e.g., amphetamines,phenylpropanolamine, phenylpropanolamine hydrochloride, or caffeine;antacidics, e.g., calcium carbonate; antiasthmatics, e.g., theophylline;antidiuretics, e.g., diphenoxylate hydrochloride; agents active againstflatulence, e.g., simethecon; migraine agents, e.g., ergotaminetartrate;psychopharmacological agents, e.g., haloperidol; spasmolytics orsedatives, e.g., phenobarbitol; antihyperkinetics, e.g., methyldopa ormethylphenidate; tranquilizers, e.g., benzodiazepines,hydroxinmeprobramates or phenothiazines; antihistaminics, e.g.,astemizol, chloropheniramine maleate, pyridamine maleate, doxlaminesuccinate, bromopheniramine maleate, phenyltoloxamine citrate,chlorocyclizine hydrochloride, pheniramine maleate, and phenindaminetartrate; decongestants, e.g., phenylpropanolamine hydrochloride,phenylephrine hydrochloride, pseudoephedrine hydrochloride,pseudoephedrine sulfate, phenylpropanolamine bitartrate, and ephedrine;beta-receptor blockers, e.g., propanolol; agents for alcohol withdrawal,e.g., disulfuram; antitussives, e.g., benzocaine, dextromethorphan,dextromethorphan hydrobromide, noscapine, carbetapentane citrate, andchlophedianol hydrochloride; fluorine supplements, e.g., sodiumfluoride; local antibiotics, e.g., tetracycline or cleocine;corticosteroid supplements, e.g., prednisone or prednisolone; agentsagainst goiter formation, e.g., colchicine or allopurinol;antiepileptics, e.g., phenyloine sodium; agents against dehydration,e.g., electrolyte supplements; antiseptics, e.g., cetylpyridiniumchloride; NSAIDs, e.g., acetaminophen, ibuprofen, naproxen, or saltsthereof; gastrointestinal active agents, e.g., loperamide andfamotidine; various alkaloids, e.g., codeine phosphate, codeine sulfate,or morphine; supplements for trace elements, e.g., sodium chloride, zincchloride, calcium carbonate, magnesium oxide, and other alkali metalsalts and alkali earth metal salts; vitamins; ion-exchange resins, e.g.,cholestyramine; cholesterol-depressant and lipid-lowering substances;antiarrhythmics, e.g., N-acetylprocainamide; and expectorants, e.g.,guaifenesin.

Active substances which have a particularly unpleasant taste includeantibacterial agents such as ciprofloxacin, ofloxacin, and pefloxacin;antiepileptics such as zonisamide; macrolide antibiotics such aserythromycin; beta-lactam antibiotics such as penicillins andcephalosporins; psychotropic active substances such as chlorpromazine;active substances such as sulpyrine; and agents active against ulcers,such as cimetidine.

In another embodiment, the method of enhancing the sweet taste of apharmaceutical composition comprises administering a pharmaceuticalcomposition comprising a sweet tastant, one or more compounds accordingto Formula I and at least one amino acid selected from the groupconsisting of glycine, L-alanine, L-arginine, L-aspartic acid,L-cystine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine,L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine,L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine,creatine, and mixtures thereof.

In a further embodiment of the present invention, the pharmaceuticalproduct comprises one sweet tastant. In another embodiment, thepharmaceutical product comprises more than one sweet tastant. In anotherembodiment, the pharmaceutical product comprises sucrose and corn syrupas sweet tastants, or sucrose and aspartame, or saccharin and sucralose.In one embodiment, the food product comprises one sweet tastant. Inanother embodiment, the food product comprises more than one sweettastant. In certain embodiments, the food product comprises sucrose andcorn syrup, or sucrose and aspartame, or saccharin and sucralose assweet tastants. In another embodiment, the pharmaceutical compositioncontains a sweet tastant selected from sugar, (sucrose), dextrose,maltose, dextrin, dried invert sugar, fructose, levulose, lactose,galactose, corn syrup, malodextrin, honey, sugar alcohols such assorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starchhydrolysates, maltitol and the like, thaumatin, aspartame, acesulfame K,saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt, spraydried licorice root, glycyrrhizin, sodium gluconate,glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®, EQUAL®, SWEET'N LOW®, and NUTRASWEET®.

The method of enhancing the sweet taste of a pharmaceutical compositioncomprises administering pharmaceutical compositions in any form suitableto achieve their intended purpose. Preferably, however, the compositionis one which can be administered buccally or orally. Alternatively, thepharmaceutical composition may be an oral or nasal spray.

The method of enhancing the sweet taste of a pharmaceutical compositioncomprises administering a pharmaceutical composition in any formsuitable for administration to any animal that can experience thebeneficial effects of one or more compounds according to Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above. Foremost among such animals are humans, although theinvention is not intended to be so limited. Other suitable animalsinclude canines, felines, dogs, cats, livestock, horses, cattle, sheep,and the like. A veterinary composition, as used herein, refers to apharmaceutical composition that suitable for non-human animals. Suchveterinary compositions are known in the art.

In another embodiment, the pharmaceutical composition in which the tasteis enhanced is selected from a liquid dosage forms for oraladministration, including pharmaceutically acceptable emulsions,solutions, suspensions, syrups, and elixirs. In addition to the activecompounds, the liquid dosage forms may contain inert diluents commonlyused in the art such as, for example, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

In a further embodiment, the invention is directed to method ofenhancing the sweet taste of a chewable tablet comprising administeringto a subject a chewable tablet comprising a sweet tastant, one or morecompounds according to Formula I, and one or more biologically activeagents. Chewable tablets are known in the art. See, e.g., U.S. Pat. Nos.4,684,534 and 6,060,078, each of which is incorporated by reference inits entirety. Any kind of medicament may be contained in the chewabletablet, preferably a medicament of bitter taste, natural plant extractsor other organic compounds. More preferably, vitamins such as vitamin A,vitamin B, vitamin B₁, vitamin B₂, vitamin B₆, vitamin C, vitamin E andvitamin K; natural plant extracts such as Sohgunjung-tang extracts,Sipchundaebo-tang extracts and Eleutherococcus senticosus extracts;organic compounds such as dimenhydrinate, meclazine, acetaminophen,aspirin, phenylpropanolamine, and cetylpyridinium chloride; orgastrointestinal agents such as dried aluminum hydroxide gel,domperidone, soluble azulene, L-glutamine and hydrotalcite may becontained in the core.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of an orally disintegrating compositioncomprising administering to a subject an orally disintegratingcomposition wherein said orally disintegrating composition comprises asweet tastant and one or more compounds according to Formula I, or anyof the specific subgroups, subclasses, or specific compounds describedabove. Orally disintegrating tablets are known in the art. See, e.g.,U.S. Pat. Nos. 6,368,625 and 6,316,029, each of which is herebyincorporated by reference in its entirety.

In another embodiment, the present invention is further directed to amethod of enhancing the sweet taste of a nasal composition comprisingadministering to a subject a nasal composition comprising a sweettastant and one or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above.Nasal sprays are known in the art. See, e.g., U.S. Pat. No. 6,187,332.Addition of one or more compounds according to Formula I to a nasalspray can reduce the experience of an unpleasant taste associated withthe composition of the nasal spray. By way of a nonlimiting example, anasal spray composition according to the present invention compriseswater (such as 95-98 weight percent), a citrate (such as 0.02 M citrateanion to 0.06 M citrate anion), a compound according to Formula I, andoptionally phosphate (such as 0.03 M phosphate to 0.09 M phosphate).

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a solid dosage form, comprisingadministering to a subject a solid dosage form comprising a water and/orsaliva activated effervescent granule, such as one having a controllablerate of effervescence, a sweet tastant, and a compound according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above. The effervescent composition may furthercomprise a pharmaceutically active compound. Effervescent pharmaceuticalcompositions are known in the art. See, e.g., U.S. Pat. No. 6,649,186,which is incorporated by reference in its entirety. The effervescentcomposition can be used in pharmaceutical, veterinary, horticultural,household, food, culinary, pesticidal, agricultural, cosmetic,herbicidal, industrial, cleansing, confectionery and flavoringapplications. Formulations incorporating the effervescent compositioncomprising a compound according to Formula I can further include one ormore additional adjuvants and/or active ingredients which can be chosenfrom those known in the art including flavors, diluents, colors,binders, filler, surfactant, disintegrant, stabilizer, compactionvehicles, and non-effervescent disintegrants.

In another embodiment, the present invention is directed a method ofenhancing the sweet taste of a film-shaped or wafer-shapedpharmaceutical composition, comprising administering to a subject afilm-shaped or wafer-shaped pharmaceutical composition that comprises asweet tastant and a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,and is capable of disintegrating. Such a film-shaped or wafer-shapedpharmaceutical composition can be configured, for example, as quicklydisintegrating administration forms, e.g., administration formsdisintegrating within a period of 1 second up to 3 minutes, or as slowlydisintegrating administration forms, e.g., administration formsdisintegrating within a period of 3 to 15 minutes.

The indicated disintegration times can be set to the above-mentionedranges by using, for example, matrix-forming polymers which havedifferent disintegrating, or solubility, characteristics. Thus, bymixing the corresponding polymer components, the disintegration time canbe adjusted. In addition, disintegrants are known which “draw” waterinto the matrix and cause the matrix to burst open from within. As aconsequence, certain embodiments of the invention include suchdisintegrants for the purpose of adjusting the disintegration time.

Suitable are polymers for use in the film-shaped or wafer-shapedpharmaceutical composition include cellulose derivatives, polyvinylalcohol (e.g. MOWIOL™) polyacrylates, polyvinyl pyrrolidone, celluloseethers, such as ethyl cellulose, as well as polyvinyl alcohol,polyurethane, polymethacrylates, polymethyl methacrylates andderivatives and copolymerisates of the aforementioned polymers.

In certain embodiments, the total thickness of the film-shaped orwafer-shaped pharmaceutical composition according to the invention ispreferably 5 μM up to 10 mm, preferably 30 μm to 2 mm, and withparticular preference 0.1 mm to 1 mm. The pharmaceutical preparationsmay round, oval, elliptic, triangular, quadrangular or polygonal shape,but they may also have any rounded shape.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a composition comprising a medicament oragent contained in a coating that surrounds a gum base formulationcomprising administering the composition, a sweet tastant and asweetness-enhancing amount of a compound according to Formula I, or anyof the specific subgroups, subclasses, or specific compounds describedabove. Preferably, the coating comprises at least 50% by weight of theentire product. As the center is chewed, the medicament or agent isreleased into the saliva. For example, U.S. Pat. No. 6,773,716, which isincorporated herein by reference in its entirety, discloses a suitablemedicament or agent contained in a coating that surrounds a gum baseformulation. One or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,can be used in preparing the coating. Optionally, the composition mayfurther comprise high-intensity sweeteners and appropriate flavors. Ithas been found that with respect to certain medicaments or agents thatmay have an astringent or bitter taste that by adding a sweetenerenhancing agent to the formulation, that a much more palatableformulation, including the medicament, can be provided. In this regard,even though the medicament in, for example, its powder form may bebitter or have an offensive taste, the matrix used as the coating of thepresent invention, including the inhibiting agent, will afford a producthaving acceptable medicinal properties.

In a further embodiment, the invention is directed to a method ofenhancing the sweet taste of a pharmaceutical composition suitable foraerosol administration, comprising administering to a subject, apharmaceutical composition suitable for aerosol administrationcomprising a sweet tastant and a compound according to Formula I, or anyof the specific subgroups, subclasses, or specific compounds describedabove, and a suitable carrier. The aerosol composition may furthercomprises pharmaceutically active agent. Aerosol compositions are knownin the art. See, e.g., U.S. Pat. No. 5,011,678, which is herebyincorporated by reference in its entirety. As a nonlimiting example, anaerosol composition according to the present invention may comprise amedically effective amount of a pharmaceutically active substance, oneor more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, and abiocompatible propellant, such as a (hydro/fluoro)carbon propellant.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a nutritional composition comprisingadministering a nutritional composition comprising a sweet tastant andone or more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, andoptionally one or more carriers. Examples of nutritional compositionshaving an undesirable taste include, but are not necessarily limited to,enteral nutrition products for treatment of nutritional deficit, trauma,surgery, Crohn's disease, renal disease, hypertension, obesity and thelike, to promote athletic performance, muscle enhancement or generalwell being or inborn errors of metabolism such as phenylketonuria. Inparticular, such nutritional formulations may contain one or more aminoacids which have a bitter or metallic taste or aftertaste. Such aminoacids include, but are not limited to, an essential amino acids selectedfrom the group consisting of L isomers of leucine, isoleucine,histidine, lysine, methionine, phenylalanine, threonine, tryptophan,tyrosine, and valine.

In certain embodiments, the administered pharmaceutical or comprises thecompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, in an amount rangingfrom about 0.001% to about 50% by weight, preferably about 0.1% to about10% by weight, or alternatively, from 0.1% to about 1% by weight. Thepresent invention also contemplates an amount of about 1% to about 20%,preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of thepharmaceutical or nutritional composition.

In various embodiments, the method comprises administering the compoundaccording to Formula I in an amount from about 0.01 mg to about 100 mgper 100 mL of the composition, or in an amount from about 0.01 mg toabout 10 mg per 100 mL of the composition. Alternatively, the compoundis administered an amount of about 0.1 mg/L to about 100 mg/L and thesweet tastant is administered in an amount of 10 g/L to 100 g/L, or inan amount ranging from 10⁻⁴% to 10⁻¹% of the sweet tastant by weight, orthe compound according to Formula I and the sweet tastant areadministered in a ratio ranging from 1:10⁶ to 1:10³.

In each of the embodiments of the methods described herein, a compoundof Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used in varying ratios to the tastant,i.e. the agent that is believed to cause the sweet taste. For example, apharmaceutical or nutritional composition of the invention may comprisea compound of Formula I in a molar ratio of about 1:10⁶ to, oralternatively administered in a molar ratio of about 1:10⁵, about 1:10⁴,about 1:10³, about 1:10², relative to the tastant. As will beappreciated, the various ranges and amounts of the compound of Formula Ican be used, with modifications if preferred, in each of the embodimentsdescribed herein. The composition may also comprise 10⁻⁴% to 10⁻¹% ofthe compound of Formula I relative to the sweet tastant, by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the pharmaceutical composition or nutritional composition inan amount ranging from about 0.001 mg to about 10 g per serving,preferably about 0.01 mg to about 5 g per serving, or alternatively,from 0.05 mg to about 1 g per serving. The present invention alsocontemplates compositions with amounts of the compound of Formula I ofabout 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg,500 mg, 1 g, 2 g, 5 g and 8 g per serving.

The method may be performed such that the sweet taste of thepharmaceutical composition or nutritional composition being enhanced bythe compound of Formula I is enhanced by at least about 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, oralternatively from about 20% to about 50%. Thus, in a more specificembodiment, the method comprises administering a pharmaceuticalcomposition or nutritional composition comprising one or more foodingredients and one or more compounds according to Formula I, whereinthe one or more compounds according to Formula I are present in anamount sufficient to enhance a sweet taste, produced by the tastant inpharmaceutical composition or nutritional composition by at least about10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60%to about 99%, or alternatively from about 30% to about 70%. Of course,in other embodiments, the sweetness may be enhanced to differingextents.

Any amount of the compound of Formula I that provides the desired degreeof sweetness enhancement can be used. For example, a compound of FormulaI may be used at a concentration of about 30 μg/L to about 1.5 g/L toenhance a sweet taste. Alternatively, concentrations of about 0.1 mg/Lto 100 mg/L of a compound of Formula I may be used to enhance a sweettaste.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a dental hygienic composition comprisingadministering a dental hygienic composition comprising a sweet tastantand one or more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above. Dentalhygienic compositions are known in the art and include but are notnecessarily limited to toothpaste, mouthwash, plaque rinse, dentalfloss, dental pain relievers (such as ANBESOL™), and the like. Incertain embodiments, the one or more compounds according to Formula Iare present in the dental hygienic composition in an amount of about 1%to about 20%, preferably about 1% to about 5%, or about 5%, 10%, or 15%,by weight. In one embodiment, the dental hygienic composition comprisesmore than one sweet tastant. In certain embodiments, the hygieniccomposition comprises sucrose and corn syrup, or it comprises sucroseand aspartame, or it comprises saccharin and sucralose as sweettastants.

In another embodiment, the present invention is directed to a method ofenhancing the sweet taste of a cosmetic product comprising administeringto a subject a cosmetic product comprising a sweet tastant and one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above. For example, but notby way of limitation, the cosmetic product comprising a compoundaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, may be a face cream, lipstick, lipgloss, and the like. In certain embodiments, the one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, are added to a cosmetic product inan amount of about 1% to about 20%, preferably about 1% to about 5%, orabout 1%, 2%, or 3%, by weight. Other suitable compositions of theinvention include lip balm, such as CHAPSTICK® or BURT'S BEESWAX® LipBalm, further comprising one or more compounds according to Formula I,or any of the specific subgroups, subclasses, or specific compoundsdescribed above.

The method of the present invention in its various embodiments may alsobe used to mask one or more tastes selected from the group consisting ofbitter, sour, salty, or umami. Preferably, the method of the presentinvention inhibits a bitter taste.

As used herein, the phrase “mask a taste” and grammatical variantsthereof, such as “masking,” refers to interfering with the perception ofa taste. The taste may be sensed to a lesser degree or not sensed at allby application of the present invention.

In another embodiment, a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,is useful for masking a taste, such as an undesirable taste of a foodproduct by creating a sweet taste. Examples of food products having anundesirable taste include, but are not necessarily limited to, citrusfruits such as grapefruit, orange, and lemon; vegetables such as tomato,pimento, celery, melon, carrot, potato and asparagus; seasoning orflavoring materials, such as soy sauce and red pepper; soybean products;fish products; meats and processed meats; dairy products such as cheese;breads and cakes; and confectioneries such as candies, chewing gum andchocolate. Other examples of food products envisioned in accordance withthe present invention are described below and throughout thespecification.

In another embodiment, the present invention is directed to a method ofmasking an undesirable taste of food product comprising administering toa subject a food product comprising a sweet tastant and one or morecompounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above. Preferably, the foodproduct is one which exhibits an desirable taste, which can be masked bya compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above. Furthermore, in apreferred embodiment, the food product comprises a compound of FormulaI, or any of the specific subgroups, subclasses, or specific compoundsdescribed above in an amount sufficient to mask an undesirable taste.

Specific food products to which one of more compounds of Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above, can be added include but are not necessarily limitedto, potassium chloride, ammonium chloride, sodium chloride (e.g., tablesalt), magnesium chloride, halide salts, naringin, caffeine, urea,magnesium sulfate, acetosulfames, aspirin, potassium benzoate, potassiumbicarbonate, potassium carbonate, potassium nitrate, potassium nitrite,potassium sulfate, potassium sulfite, potassium glutamate, foodpreservatives in their physiologically acceptable salts, antibiotics,unsweetened chocolate, cocoa beans, yogurt, preservatives, flavorenhancers, dietary supplements, gelling agents, pH control agents,nutrients, processing aids, bodying agents, dispersing agents,stabilizers, colorings, coloring diluents, anticaking agents,antimicrobial agents, formulation aids, leavening agents, surface activeagents, anticaking agents, nutrient supplements, alkali, acids,sequestrants, denuding agents, general purpose buffers, thickeners,cooked out juice retention agents, color fixatives in meat and meatproducts, color fixatives in poultry and poultry products, doughconditioners, maturing agents, yeast foods, mold retardants,emulsifiers, texturizers, binders, water correctives, miscellaneous andgeneral purpose food additives, tableting aids, lye peeling agents,washing water agents, oxidizers, antioxidants, enzymes, extenders,fungicides, cake mixes, coffee, tea, dry mixes, non-dairy creamers,salts, animal glue adjuvant, cheese, nuts, meat and meat products,poultry and poultry product, pork and pork products, fish and fishproducts, vegetable and vegetable products, fruit and fruit products,smoked products such as meat, cheese fish, poultry, and vegetables,whipping agents, masticatory substances in chewing gums, doughstrengtheners, animal feed, poultry feed, fish feed, pork feed,defoaming agents, juices, liquors, substances or drinks containingalcohol, beverages including but not limited to alcoholic beverages andnon-alcoholic carbonated and/or non-carbonated soft drinks, whippedtoppings, bulking agents used in eatables including but not limited tostarches, corn solids, polysaccharides and other polymericcarbohydrates, icings, as well as potassium-containing ormetal-containing substances with undesirable tastes and the like. Thecompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.001% to about 50% by weight,preferably about 0.1% to about 10% by weight, or alternatively, from0.1% to about 1% by weight. The present invention also contemplates anamount of about 1% to about 20%, preferably about 1% to about 5%, about1%, 3%, or 4%, by weight, of the composition

The method may be performed such that the taste of the food productbeing masked by the compound of Formula I is reduced by at least about10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60%to about 99%, or alternatively from about 20% to about 50%. Thus, in amore specific embodiment, the method comprises administering a foodproduct comprising one or more food ingredients and one or morecompounds according to Formula I, wherein the one or more compoundsaccording to Formula I are present in an amount sufficient to mask abitter taste, produced by the food product, by at least about 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about99%, or alternatively from about 30% to about 70%. Of course, in otherembodiments, a taste may be masked to differing extents.

Any amount of the compound of Formula I that provides the desired degreeof taste masking can be used. For example, a compound of Formula I maybe used at a concentration of about 30 μg/L to about 1.5 g/L to mask abitter taste. Alternatively, concentrations of about 0.1 mg/L to 100mg/L of a compound of Formula I may be used to mask an undesirabletaste.

A food product may also include beverages and drinks. Examples ofsuitable beverages include, but are not limited to coffee, teas, such asblack tea, green tea, fermented tea, semi-fermented tea, carbonated softdrinks, such as COKE® and PEPSI®, non-carbonated soft drinks, lemonade,juices and other fruit drinks, sports drinks, such as GATORADE®, icedteas, coca, alcoholic beverages, such as beers, wines and liquors, andKOOL-AID.® In certain embodiments, the taste masking effective amount ofa compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, has a range of fromabout 0.001 to about 5.0 grams per 100 mL. In other embodiments, thetaste masking effective amount of a compound according to Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above, has a range of from about 0.5 to about 2 grams per 100mL. Alternatively, a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,is administered in an amount of about 1 gram per 100 mL. It iscontemplated that between 0.1 mg/L and 100 mg/L of the compound ofFormula I is present and between 10 g/L and 100 g/L of sweet tastant ispresent. For example, a composition could contain 0.1 mg/L, 1 mg/L, or10 mg/L of the compound of Formula I and 10 mg/L of the tastant.Alternatively, the composition could contain 0.5 mg/L, 5 mg/L, or 50mg/L of the compound of Formula I and 50 mg/L of the tastant. In otherembodiments, the composition contains 1 mg/L, 10 mg/L or 100 mg/L of thecompound of Formula I and 100 g/L of the tastant.

In another embodiment, the present invention is directed to a method ofincreasing the palatability and/or intake of food, comprisingadministering to a subject in need of such treatment a food productcomprising a sweet tastant and one or more compounds according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, in an amount sufficient to increase thepalatability and/or intake of food. Thus, according to the presentinvention, a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, may beadministered to a subject so that the palatability of food, asexperienced by said subject, is increased. Without being bound bytheory, it is believed that a higher palatability of food can lead to agreater intake of food by the subject. Thus, in certain embodiments, byadministering a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, to asubject, the subject will consume an increased amount of food comparedto the subject's food intake when not being administered a compound ofFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above. In other embodiments, by administering acompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, to a subject, thesubject will have a higher caloric intake compared to the subject'scaloric intake when not being administered a compound of Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above. In other embodiments, administering a compoundaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, to a subject can be means toovercome taste impairment associated with radiation treatments forcancer, with certain drugs and loss of taste sensations in the elderly.

In each of the embodiments of methods described above, the subject ofthe method, unless otherwise limited to, may be any animal which is needof the particular treatment or effect of the method. Such animalsinclude but are not limited to a cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit, monkey, or guinea pig tastemodulating protein. In other embodiments, the animal is a livestockanimal, a domesticated animal, or an animal kept as a pet. In particularembodiments, the subject of the claimed method is a human.

Furthermore, in each of the embodiments of the methods described herein,a compound of Formula I may be used in varying ratios to the agent thatis believed to cause the unwanted taste, such as a bitter taste. Forexample, a composition of the invention may comprise a compound ofFormula I in a molar ratio of about 0.001:1 to about 10:1, oralternatively administered in a molar ratio of about 0.01:1, about0.02:1, about 0.05:1, about 0.1:1, or about 0.5:1, relative to the agentcausing the unwanted taste. As will be appreciated, the various rangesand amounts of the compound of Formula I can be used, with modificationsif preferred, in each of the embodiments described herein.

In another example, the present invention is directed to a method ofmasking the bitter taste of a pharmaceutical composition, comprisingadministering to a subject in need of such method a pharmaceuticalcomposition comprising a sweet tastant and a compound according toFormula I, wherein the pharmaceutical composition comprises apharmaceutically active agent and optionally one or more excipients, andwherein the compound according to Formula I is administered as either acomponent of the pharmaceutical composition or as a separate dosageform, and wherein the molar ratio of the compound of Formula I to thepharmaceutically active agent is about 1:10⁶ to about 10:1, oralternatively administered in a molar ratio of about 1:10⁵, about 1:10⁴,about 1:10³, or about 1:10², relative to the tastant. As will beappreciated, the various ranges and amounts of the compound of Formula Ican be used, with modifications if preferred, in each of the embodimentsdescribed herein.

In certain embodiments, a single dose or two to four divided dailydoses, provided on a basis of about 0.001 to 100 mg per kilogram of bodyweight per day, preferably about 0.01 to about 25 mg/kg of body weightper day is appropriate. When enhancing a taste receptor cell in vivo,the compound of Formula I is preferably administered orally.

An additional aspect of the present invention is a method of masking theundesirable of a pharmaceutical composition, comprising administeringpharmaceutical composition comprising a sweet tastant and a compoundaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, to a subject receiving thepharmaceutical composition. The compound of Formula I may beadministered together with the pharmaceutical composition as separatecompositions, for example either concurrently or sequentially. Thecompound of Formula I may administered, or caused to be administered,prior to the pharmaceutical agent producing the taste to be enhanced ormasked. Alternatively, the compound for Formula I may be administered asa component of the pharmaceutical composition.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the composition in an amount ranging from about 0.0001 mg toabout 500 mg per dose, preferably about 0.001 mg to about 100 mg, oralternatively, from 0.05 mg to about 10 mg per dose. The presentinvention also contemplates compositions with amounts of the compound ofFormula I of about 0.0001 mg, 0.0005 mg, 0.001 mg, 0.005 mg, 0.01 mg,0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500 mgper dose.

By way of additional examples, the method of masking the taste of apharmaceutical composition may comprise masking a taste produced by oneor more agents selected from the group consisting of antipyretics,analgesics, laxatives, appetite depressants, antacidics, antiasthmatics,antidiuretics, agents active against flatulence, antimigraine agents,psychopharmacological agents, spasmolytics, sedatives,antihyperkinetics, tranquilizers, antihistaminics, decongestants,beta-receptor blockers, agents for alcohol withdrawal, antitussives,fluorine supplements, local antibiotics, corticosteroid supplements,agents against goiter formation, antiepileptics, agents againstdehydration, antiseptics, NSAIDs, gastrointestinal active agents,alkaloids, supplements for trace elements, ion-exchange resins,cholesterol-depressant agents, lipid-lowering agents, antiarrhythmics,and expectorants. Further specific examples of pharmaceuticalcompositions in accordance with the method of the invention aredescribed below.

Additionally, the method of masking the taste of a pharmaceuticalcomposition may comprise masking a taste produced by a counterterrorismpharmaceutical. Because of the increased risk of terrorist attacks, suchas chemical, nuclear, or biological attacks, the use of counterterrorismpharmaceutical agents is expected to increase in the future. Acounterterrorism pharmaceutical agent includes those pharmaceuticalagents that are useful in counteracting agents that can be used in aterrorist attack. Agents that have been used in terrorist acts, orconsidered as useful for carrying out future terrorist acts, includericin, sarin, radioactive agents and materials, and anthrax.Pharmaceutical agents that counteract these agents are useful as acounterterrorism pharmaceutical. Such counterterrorism pharmaceuticalsinclude, but are not limited to, antibiotics such as ciprofloxacin anddoxycycline; potassium iodide; and antiviral agents. Thus, in oneembodiment of the present invention, the method may be performed suchthat the taste of a counterterrorism pharmaceutical, such as anantibiotic such as ciprofloxacin and doxycycline; potassium iodide; oran antiviral agent, is masked by the compound of Formula I by at leastabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about60% to about 99%, or alternatively from about 25% to about 50%. Inanother embodiment, the compound of Formula I is administered in a ratioof from about 10:1 to about 1:10 in relation to the counterterrorismagent.

In another embodiment, a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,is useful for masking an undesirable taste of a nutritional composition.Examples of nutritional compositions having an undesirable tasteinclude, but are not necessarily limited to, enteral nutrition productsfor treatment of nutritional deficit, trauma, surgery, Crohn's disease,renal disease, hypertension, obesity and the like, to promote athleticperformance, muscle enhancement or general well being or inborn errorsof metabolism such as phenylketonuria. In particular, such nutritionalformulations may contain one or more amino acids which have a bitter ormetallic taste or aftertaste. Such amino acids include, but are notlimited to, an essential amino acids selected from the group consistingof L isomers of leucine, isoleucine, histidine, lysine, methionine,phenylalanine, threonine, tryptophan, tyrosine, and valine. Furtherspecific examples of nutritional compositions in accordance with themethod of the invention are described below.

In one embodiment, the nutritional composition comprises one sweettastant. In another embodiment, the nutritional composition comprisesmore than one sweet tastant. In certain embodiments, the nutritionalcomposition comprises sucrose and corn syrup, or sucrose and aspartame,or saccharin and sucralose as sweet tastants. In another embodiment, thenutritional composition contains a sweet tastant selected from sugar,(sucrose), dextrose, maltose, dextrin, dried invert sugar, fructose,levulose, lactose, galactose, corn syrup, malodextrin, honey, sugaralcohols such as sorbitol, mannitol, xylitol, lactitol, malitol,hydrogenated starch hydrolysates, maltitol and the like, thaumatin,aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl maltol,glycine, isomalt, spray dried licorice root, glycyrrhizin, sodiumgluconate, glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®,EQUAL®, SWEET 'N LOW®, and NUTRASWEET®.

By way of example, the method may be performed such that the taste beingmasked by the compound of Formula I is masked by at least about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% toabout 99%, or alternatively from about 20% to about 50% Thus, in a morespecific embodiment, the method comprises administering a nutritionalcomposition comprising a sweet tastant, a nutritional agent, optionallyone or more excipients, and one or more compounds according to FormulaI, wherein the one or more compounds according to Formula I are presentin an amount sufficient to mask a undesired taste, produced by thenutritional agent, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, or 95%, or from about 60% to about 99%, or alternatively fromabout 10% to about 50%.

A compound according to Formula I may be incorporated into medicaland/or dental compositions. Certain compositions used in diagnosticprocedures have an unpleasant taste, such as contrast materials andlocal oral anesthetics. The enhancers of the invention may be used toimprove the comfort of subjects undergoing such procedures by improvingthe taste of compositions. In addition, the enhancers of the inventionmay be incorporated into pharmaceutical compositions, including tabletsand liquids, to improve their flavor and improve patient complianceparticularly where the patient is a child or a non-human animal).

In another embodiment, a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,is used to enhance the taste of a cosmetic product. For example, but notby way of limitation, a compound according to Formula I may beincorporated into face creams, lipsticks, lip gloss, and the like. Also,a compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be used to maskan unpleasant taste of lip balm, such as CHAPSTICK® or BURT'S BEESWAX®Lip Balm.

In addition, a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, may beincorporated into compositions that are not traditional foods,pharmaceuticals, or cosmetics, but which may contact taste membranes.Examples include, but are not limited to, soaps, shampoos, toothpaste,denture adhesive, and glue on the surfaces of stamps and envelopes.Thus, the present invention also covers a process of preparing acomposition that is not a traditional food, pharmaceutical, or cosmetic,but which may contact taste membranes, according to conventionalmethods, wherein the improvement comprises adding a compound of FormulaI to said composition.

In another embodiment, a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,is used to mask the taste associated with one or more the following:bitter pharmaceutical alkaloids such as acetaminophen, ampicillin,chlorpheniramine, chlarithromycin, doxylamine, guaifenesin, ibuprofen,pseudoephedrine hydrochloride, and ranitidine, bitter pharmaceuticalmetallic salts such as zinc containing bioadhesives (denture adhesive),bitter vitamins, bitter components of foods such as creatine, limonin,naringin, quinizolate, and bitter components of beverages such ascaffeine, and humulone. In one embodiment, the concentration of thecompound according to Formula I used is in the range of 0.01 mM to 20 mMand may vary depending on the amount of bitter compound used and itsbitterness.

In another embodiment, the present invention is directed to a method ofmasking the taste of a veterinary product, such as veterinary medicines,veterinary food products, veterinary supplements, and the like, that areadministered to domesticated animals. In a preferred embodiment, acompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, is used to mask ataste of a veterinary product administered to a cat or dog.

In one embodiment, in each of the methods of masking a taste describedherein, a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, isadministered in an amount effective to mask said taste. As a nonlimitingexample, the taste masking effective amount of a compound according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, administered in one embodiment is from about0.01 to about 5.0 grams per 100 mL.

In one embodiment, the present invention is directed to a method ofmasking the taste of a pharmaceutical product, comprising administeringto a subject a pharmaceutical product comprising a sweet tastant and acompound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, is administered in anamount that is sufficient, in combination with the administration of oneor more additional sweetening agents, to enhance said taste. Forexample, in a method enhancing the sweet taste in a liquidpharmaceutical composition, the composition comprises a sweet tastantand a compound according to Formula I and another sweetening agent,wherein the amount of the compound of Formula I is about 25% to about75% of the amount required to inhibit the bitter taste in the absence ofthe other taste inhibiting agent. Suitable sweetening agents include butare not limited to sugar, (sucrose), dextrose, maltose, dextrin, driedinvert sugar, fructose, levulose, lactose, galactose, corn syrup,malodextrin, honey, sugar alcohols such as sorbitol, mannitol, xylitol,lactitol, malitol, hydrogenated starch hydrolysates, maltitol and thelike, thaumatin, aspartame, acesulfame K, saccharin, sucralose,glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones, zincgluconate, ethyl maltol, glycine, isomalt, spray dried licorice root,glycyrrhizin, sodium gluconate, glucono-delta-lactone, ethyl vanillin,vanillin, SPLENDA®, EQUAL®, SWEET 'N LOW®, and NUTRASWEET®.

In another embodiment the above described compounds may be used toenhance a taste modulating protein. Such inhibition may be in vitro orin vivo. The amount of the compound of Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, used toinhibit the taste modulating protein may not necessarily be the samewhen used in vivo compared to in vitro. Factors such as pharmacokineticsand pharmacodynamics of the particular compound may require that alarger or smaller amount of the compound of Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,be used when inhibiting a taste modulating protein in vivo. Accordingly,one aspect of the present invention is a method of enhancing a tastemodulating protein, comprising contacting the taste modulating proteinwith a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above.

In one embodiment of this aspect of the present invention, the methodcomprises contacting a cell with a compound of Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,wherein said cell expresses said taste modulating protein.

In another embodiment of the present invention, the method comprisesadministering a compound of Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, to a subject in anamount sufficient to inhibit a taste modulating protein, wherein saidsubject has or expresses said taste modulating protein. Furthermore,when administered orally, the compound may be dispersed or diluted bysaliva.

The present invention is directed to a method of enhancing a tastemodulating protein, comprising contacting said protein with a compoundof Formula I, or any of the specific subclasses and specific compoundslisted above, and enhancing the protein by at least about 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%. Inanother embodiment, the method comprises contacting said protein with acompound of Formula I, or any of the specific subclasses and specificcompounds listed above, and enhancing the protein by about 10% to about50%. In another embodiment, the present invention is directed to amethod of enhancing a taste modulating protein, comprising contactingsaid protein with a compound of Formula I, or any of the specificsubclasses and specific compounds listed above, and enhancing theprotein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 95%, or from about 50% to about 99%, or alternatively from about 10%to about 50%, and wherein said taste modulating protein is a naturallyoccurring taste modulating protein. In another embodiment, the presentinvention is directed to a method of enhancing a taste modulatingprotein, comprising contacting said protein with a compound of FormulaI, or any of the specific subclasses or specific compounds listed above,and enhancing the protein by at least about 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, oralternatively from about 10% to about 50%, and wherein said protein is anaturally occurring human taste modulating protein.

Any amount of the compound of Formula I that provides the desired degreeof enhancement can be used. For example, a compound of Formula I may beused at a concentration of about 0.1 μM to about 1,000 μM to enhance ataste modulating protein. Alternatively, concentrations of about 1, 10or 100 μM of a compound of Formula I may be used to enhance a tastemodulating protein. In certain embodiments, a single dose or two to fourdivided daily doses, provided on a basis of about 0.001 to 100 mg perkilogram of body weight per day, preferably about 0.01 to about 25 mg/kgof body weight per day is appropriate. The substance is preferablyadministered orally, but parenteral routes such as the subcutaneous,intramuscular, intravenous or intraperitoneal routes or any othersuitable delivery system, such as intranasal or transdermal routes canalso be employed.

As used herein, the term “enhancing” and grammatical variants thereofrefers to interfering with the normal activity of. For example,enhancing a taste modulating protein means interfering with the normalactivity of a taste modulating protein. Enhancing includes but is notnecessarily limited to modulating, modifying, activating, and the like.

As used herein, the phrase “taste modulating protein” refers to a TRPM5protein, and includes naturally and recombinantly produced TRPM5proteins; natural, synthetic, and recombinant biologically activepolypeptide fragments of said protein; biologically active polypeptidevariants of said protein or fragments thereof, including hybrid fusionproteins and dimers; biologically active polypeptide analogs of saidprotein or fragments or variants thereof, including cysteine substitutedanalogs. The taste modulating protein may be a nonhuman protein, forexample a nonhuman mammalian protein, or in other embodiments a nonhumanprotein such as but not limited to a cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit, monkey, or guinea pig tastemodulating protein. The taste modulating protein may be generated and/orisolated by any means known in the art. An example of the tastemodulating protein and methods of producing the protein are disclosedin, for example, Liu and Liman, Proc. Nat'l Acad. Sci. USA 100:15160-15165 (2003); D. Prawitt, et al., Proc. Nat'l Acad. Sci. USA 100:15166-71 (2003); and Ulrich, N. D., et al., Cell Calcium 37: 267-278(2005); each of which is fully incorporated by reference herein.

A homologue is a protein that may include one or more amino acidsubstitutions, deletions, or additions, either from natural mutations ofhuman manipulation. Thus, by way of example, a taste modulating proteinmay include one or more amino acid substitutions, deletions oradditions, either from natural mutations or human manipulation. Asindicated, changes are preferably of a minor nature, such asconservative amino acid substitutions that do not significantly affectthe folding or activity of the protein.

The variant taste modulating proteins which may be enhanced inaccordance with the present invention comprise non-conservativemodifications (e.g., substitutions). By “nonconservative” modificationherein is meant a modification in which the wild-type residue and themutant residue differ significantly in one or more physical properties,including hydrophobicity, charge, size, and shape. For example,modifications from a polar residue to a nonpolar residue or vice-versa,modifications from positively charged residues to negatively chargedresidues or vice versa, and modifications from large residues to smallresidues or vice versa are nonconservative modifications. For example,substitutions may be made which more significantly affect: the structureof the polypeptide backbone in the area of the alteration, for examplethe alpha-helical or beta-sheet structure; the charge or hydrophobicityof the molecule at the target site; or the bulk of the side chain. Thesubstitutions which in general are expected to produce the greatestchanges in the polypeptide's properties are those in which (a) ahydrophilic residue, e.g., seryl or threonyl, is substituted for (or by)a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl oralanyl; (b) a cysteine or proline is substituted for (or by) any otherresidue; (c) a residue having an electropositive side chain, e.g.,lysyl, arginyl, or histidyl, is substituted for (or by) anelectronegative residue, e.g., glutamyl or aspartyl; or (d) a residuehaving a bulky side chain, e.g., phenylalanine, is substituted for (orby) one not having a side chain, e.g., glycine. In one embodiment, thevariant taste modulating proteins used in accordance with the presentinvention have at least one nonconservative modification.

In other embodiments, the method of the invention comprises enhancing ataste modulating protein that is a nonhuman protein, such as but notlimited to a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, monkey, or guinea pig taste modulating protein.

In other instances, the method comprises administering the compoundaccording to Formula I as a food composition, a pharmaceuticalcomposition, or a veterinary composition, e.g., wherein the compound isin a concentration from about 1% to about 10% on a weight percentagebasis, or in an amount of about 0.01 mg to about 10 mg per mL.

An additional aspect of the present invention is a method of enhancingthe depolarization of a taste receptor cell, comprising contacting thetaste receptor cell with a compound according to Formula I, or any ofthe specific subgroups, subclasses, or specific compounds describedabove. For example, a compound of Formula I may enhance thedepolarization of a taste receptor cell by a mechanism other than, or inaddition to, the mechanism of enhancing a taste receptor protein. In oneembodiment of this aspect of the present invention, the method comprisescontacting a taste receptor cell with a compound of Formula I, or any ofthe specific subgroups, subclasses, or specific compounds describedabove, wherein said taste receptor cell can detect a sweet taste. Inanother embodiment of the present invention, the method comprisesadministering a compound of Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, to a subject in anamount sufficient to enhance the depolarization of a taste receptorcell. Furthermore, when administered orally, the compound may bedispersed or diluted by saliva.

By way of example, the present invention is directed to a method ofenhancing the depolarization of a taste receptor cell, comprisingcontacting said taste receptor cell with a compound of Formula I, or anyof the specific subclasses and specific compounds listed above, andenhancing the depolarization of the taste receptor cell by at leastabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about60% to about 99%, or alternatively from about 30% to about 75%. Inanother embodiment, the present invention is directed to a method ofenhancing the depolarization of a taste receptor cell, comprisingcontacting said protein with a compound of Formula I, or any of thespecific subclasses and specific compounds listed above, and enhancingthe depolarization of the taste receptor cell by at least about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% toabout 99%, or alternatively from about 20% to about 60%, and whereinsaid taste receptor cell is a naturally occurring taste modulatingprotein. In another embodiment, the present invention is directed to amethod of enhancing a taste receptor cell, comprising contacting saidprotein with a compound of Formula I, or any of the specific subclassesor specific compounds listed above, and enhancing the taste receptorcell by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or95%, or from about 50% to about 99%, or alternatively from about 40% toabout 80%, and wherein said taste receptor cell is a human tastereceptor cell.

Any amount of the compound of Formula I that provides the desired degreeof enhancement can be used. For example, a compound of Formula I may beused at a concentration of about 0.1 μM to about 1,000 μM to enhance ataste receptor cell. Alternatively, concentrations of about 1 μM, 50 μM,or 100 μM of a compound of Formula I may be used to enhance thedepolarization of a taste receptor cell.

In certain embodiments, a single dose or two to four divided dailydoses, provided on a basis of about 0.001 to 100 mg per kilogram of bodyweight per day, preferably about 0.01 to about 25 mg/kg of body weightper day is appropriate. When enhancing a taste receptor cell in vivo,the compound of Formula I is preferably administered orally.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight.

In one embodiment of this aspect of the present invention, the methodcomprises contacting a taste receptor cell with a compound of Formula I,or any of the specific subgroups, subclasses, or specific compoundsdescribed above, wherein said taste receptor cell can detect a sweet,bitter, sour, salty, or umami taste. In another embodiment of thepresent invention, the method comprises administering a compound ofFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, to a subject in an amount sufficient toenhance the depolarization of a taste receptor cell. Furthermore, whenadministered orally, the compound may be dispersed or diluted by saliva.

Compositions

The present invention is also directed to various, useful compositionscomprising a compound of Formula I or a physiologically acceptable saltthereof.

In another embodiment, the present invention is directed to a foodproduct comprising a sweet tastant and one or more compounds accordingto Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above. Preferably, the food product is one whichexhibits a sweet taste and/or contains a sweetening agent which can beenhanced by a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above.Furthermore, in a preferred embodiment, the food product comprises acompound of Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above in an amount sufficient to enhancethe sweet taste. Specific sweetening agents to which one of morecompounds of Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, can be added to enhance its sweettaste include but are not necessarily limited to sugar, (sucrose),dextrose, maltose, dextrin, dried invert sugar, fructose, levulose,lactose, galactose, corn syrup, malodextrin, honey, sugar alcohols suchas sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starchhydrolysates, maltitol and the like, thaumatin, aspartame, acesulfame K,saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt, spraydried licorice root, glycyrrhizin, sodium gluconate,glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®, EQUAL®, SWEET'N LOW®, and NUTRASWEET®. Specific food products in which an enchantedsweet taste is desired include but are not limited to cakes, cookies,confectionaries such as candies, gums and chocolates, creams, icing, icecream, pies and breads. Specific food products which are beveragesinclude soft drinks, juices and other fruit drinks, sports drinks suchas GATORADE®, coffee, teas, iced teas, coca, alcoholic beverages andKOOL-AID®.

Specific food products to which one of more compounds of Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above, can be added include but are not necessarily limitedto, potassium chloride, ammonium chloride, sodium chloride (e.g., tablesalt), magnesium chloride, halide salts, naringin, caffeine, urea,magnesium sulfate, acetosulfames, aspirin, potassium benzoate, potassiumbicarbonate, potassium carbonate, potassium nitrate, potassium nitrite,potassium sulfate, potassium sulfite, potassium glutamate, foodpreservatives in their physiologically acceptable salts, antibiotics,unsweetened chocolate, cocoa beans, yogurt, preservatives, flavorenhancers, dietary supplements, gelling agents, pH control agents,nutrients, processing aids, bodying agents, dispersing agents,stabilizers, colorings, coloring diluents, anticaking agents,antimicrobial agents, formulation aids, leavening agents, surface activeagents, anticaking agents, nutrient supplements, alkali, acids,sequestrants, denuding agents, general purpose buffers, thickeners,cooked out juice retention agents, color fixatives in meat and meatproducts, color fixatives in poultry and poultry products, doughconditioners, maturing agents, yeast foods, mold retardants,emulsifiers, texturizers, binders, water correctives, miscellaneous andgeneral purpose food additives, tableting aids, lye peeling agents,washing water agents, oxidizers, antioxidants, enzymes, extenders,fungicides, cake mixes, coffee, tea, dry mixes, non-dairy creamers,salts, animal glue adjuvant, cheese, nuts, meat and meat products,poultry and poultry product, pork and pork products, fish and fishproducts, vegetable and vegetable products, fruit and fruit products,smoked products such as meat, cheese fish, poultry, and vegetables,whipping agents, masticatory substances in chewing gums, doughstrengtheners, animal feed, poultry feed, fish feed, pork feed,defoaming agents, juices, liquors, substances or drinks containingalcohol, beverages including but not limited to alcoholic beverages andnon-alcoholic carbonated and/or non-carbonated soft drinks, whippedtoppings, bulking agents used in eatables including but not limited tostarches, corn solids, polysaccharides and other polymericcarbohydrates, icings, as well as potassium-containing ormetal-containing substances and the like. The compound according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, can be typically present in an amount rangingfrom about 0.001% to about 50% by weight, preferably about 0.1% to about10% by weight, or alternatively, from 0.1% to about 1% by weight, of thesweet tastant. The present invention also contemplates the preparationof amount of about 1% to about 20%, preferably about 1% to about 5%,about 1%, 3%, or 4%, by weight.

In other embodiments, the food product is a liquid food product, e.g., acarbonated beverage, or a solid food product, e.g., citrus fruits;vegetables; seasoning or flavoring materials; soybean products; fishproducts; meats and processed meats; dairy products; breads and cakes;and confectioneries. A

The food product may contain the compound according to Formula I in aconcentration from about 1% to about 10% on a weight percentage basis,or in an amount from about 0.01 mg to about 100 mg per mL of foodproduct, or in an amount from about 0.01 mg to about 100 mg per gram offood product, or in an amount of about 0.1 mg/L to about 100 mg/L andthe sweet tastant is administered in an amount of 10 g/L to 100 g/L.Alternatively, the food product comprises the compound according toFormula I and the sweet tastant are administered in a ratio ranging from1:106 to 1:103, or comprises the compound according to Formula I isadministered in an amount ranging from 10⁻⁴% to 10⁻¹% of the sweettastant by weight.

In other instances, the method is such that the sweet tastant isselected from the group consisting of sugar, (sucrose), dextrose,maltose, dextrin, dried invert sugar, fructose, levulose, lactose,galactose, corn syrup, malodextrin, honey, sugar alcohols such assorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starchhydrolysates, maltitol and the like, thaumatin, aspartame, acesulfame K,saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt, spraydried licorice root, glycyrrhizin, sodium gluconate,glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®, EQUAL®, SWEET'N LOW®, NUTRASWEET®, and mixtures thereof.

In other instances, the food product comprises, consists of, or consistsessentially of a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, and one ormore sweet tastants. Such sweet tastants include sugar, (sucrose),dextrose, maltose, dextrin, dried invert sugar, fructose, levulose,lactose, galactose, corn syrup, malodextrin, honey, sugar alcohols suchas sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starchhydrolysates, maltitol and the like, thaumatin, aspartame, acesulfame K,saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt, spraydried licorice root, glycyrrhizin, sodium gluconate,glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®, EQUAL®, SWEET'N LOW®, NUTRASWEET®, and mixtures thereof.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the food product.

For example, an embodiment of the invention includes an improved colabeverage, such as COKE® or PEPSI® wherein the improvement comprises oneor more s of Formula I. Cola beverages of the invention can be preparedby mixing cola concentrate with carbonated water. Typically about 50 mLof cola concentrate is added per 250 mL of carbonated water. Colaconcentrate can be prepared by mixing cola flavor, caramel color, andoptionally caffeine with water, one or more sweet tastants, one or morecompounds of Formula I, and one or more acid components.

A cola flavor refers to either a natural or artificial flavor. Such colaflavors are commercially available. Commercial cola flavors areavailable, for example, from International Flavor and Fragrances,Dayton, N.J.; Artificial—#13573011 and Natural #K3559549. Commercialcola flavors are also available from Tastemaker, Cincinnati, Ohio, andGivaudan Roure, Clifton, N.J.

The acid component refers an ingredient that contributes sourness to thebeverage and is added to balance the flavor profile by reducing chemicalor sweetener side tastes. Acids may include malic acid, citric acid,phosphoric acid or combinations thereof.

Examples of sweet tastants include but are not limited to the groupconsisting of sugar, (sucrose), dextrose, maltose, dextrin, dried invertsugar, fructose, levulose, lactose, galactose, corn syrup, malodextrin,honey, sugar alcohols such as sorbitol, mannitol, xylitol, lactitol,malitol, hydrogenated starch hydrolysates, maltitol and the like,thaumatin, aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin,alitame, cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethylmaltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,SPLENDA®, EQUAL®, SWEET 'N LOW®, and NUTRASWEET®. Sucrose, saccharin,sucralose, and aspartame or preferred. As discussed supra, thecompositions of the invention can comprise more than one sweet tastant.For example, the food products of this invention can comprise bothsucrose and corn syrup as sweet tastants, or sucrose and aspartame assweet tastants, or saccharin and sucralose as sweet tastants.

For example, the cola concentrate can prepared by mixing phosphoric acid(75% Rhone-Poulenc), citric acid (anhydrous, ADM, Decatur, Ill.),caffeine (Mallinckrodt, Paris, Ky.), caramel Color (DS400, Sethness,Chicago, Ill.), cola Flavor (SN018976, International Flavors andFragrances, Dayton, N.J.), sucrose, one or more compounds of Formula I,and water. The concentrate is blended until all ingredients aredissolved (30-40 minutes) using a magnetic stirring plate. Fiftymilliliters of the concentrate are added to 250 mL of carbonated waterto complete the preparation of the cola beverage. Fifty milliliters ofcola concentrate typically contains from 0.01 to 5 mL of phosphoricacid, preferably about 0.01-1 mL, 0.1 to 100 g of sucrose, preferablyabout 1-10 g, about 1×10⁻⁶ g to 10 g of a compound of Formula I,preferably about 1×10⁻³ g to 1 g, about 0.001 g to 0.1 g of citric acid,preferably about 0.005-0.1 g, 0.001 to 1 g of caffeine, preferably about0.01 to 0.1 g of caffeine, 0.01 to 5 g of caramel flavor, preferablyabout 0.05 to 1 g, 0.001 to about 10 mL of cola flavor, preferably about0.01 to about 2 mL.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the cola beverage.

In each of the embodiments of the methods described herein, a compoundof Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used in varying ratios to the tastant,i.e. the agent that is believed to cause the sweet taste. For example, acomposition of the invention may comprise a compound of Formula I in amolar ratio of about 1:10⁶ to about 10:1, or alternatively administeredin a molar ratio of about 1:10⁵, about 1:10⁴, about 10:10³, about 1:10²,relative to the tastant. As will be appreciated, the various ranges andamounts of the compound of Formula I can be used, with modifications ifpreferred, in each of the embodiments described herein. The compositionmay also comprise 10⁻⁴% to 10⁻¹% of the compound of Formula I relativeto the sweet tastant, by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the cola beverage in an amount ranging from about 0.001 mg toabout 10 g per serving, preferably about 0.01 mg to about 5 g perserving, or alternatively, from 0.05 mg to about 1 g per serving. Thepresent invention also contemplates cola beverages with amounts of thecompound of Formula I of about 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 500 mg, 1 g, 2 g, 5 g and 8 g per serving.

Any amount of the compound of Formula I that provides the desired degreeof sweetness enhancement can be used. For example, a compound of FormulaI may be used at a concentration of about 30 μg/L to about 1.5 g/L toenhance a sweet taste. Alternatively, concentrations of about 0.1 to 100mg/L of a compound of Formula I may be used to enhance a sweet taste. Itis contemplated that between 0.1 mg/L and 100 mg/L of the compound ofFormula I is present and between 10 g/L and 100 g/L of sweet tastant ispresent. For example, a composition could contain 0.1 mg/L, 1 mg/L, or10/L mg of the compound of Formula I for 10 mg/L of the tastant.Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50 mg/Lof the compound of Formula I for 50 mg/L of the tastant. In otherembodiments, the composition contains 1 mg/L, 10 mg/L or 100 mg/L of thecompound of Formula I for 100 g/L of the tastant.

In certain embodiments, the improved food product such as the colabeverage, e.g., COKE® or PEPSI,® will contain a reduced amount of sugarcompared to the prior art cola beverage. The method may be performedsuch that the amount of sugar required to maintain the desired sweetnessof the cola beverage is reduced by at least about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, oralternatively from about 20% to about 50%. Thus, in a more specificembodiment, the cola beverage comprising a sweet tastant and one or morecompounds according to Formula I, contains one or more compoundsaccording to Formula I in an amount sufficient to reduce the amount ofsugar required to maintain the desired sweetness of the beverage isreduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or fromabout 60% to about 99%, or alternatively from about 30% to about 70%. Ofcourse, in other embodiments, the amount of sugar required may bedecreased to differing extents.

Additionally, the invention is directed to a process of preparing animproved food product, wherein the improvement comprises adding one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, to a food product. Incertain embodiments, the one or more compounds according to Formula I,or any of the specific subgroups, subclasses, or specific compoundsdescribed above, are added to the food product in an amount of about 1%to about 25%, about 1% to about 10%, or about 5%, 10%, or 15%, byweight. In other embodiments, the improved food product will contain areduced amount of sweet tastant, e.g., sucrose.

In another embodiment, the present invention is directed to an animalfood product comprising one or more compounds according to Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above. The one or more compounds are preferably in an amountsufficient to enhance one or more sweet tastes associated with theanimal food product. Animal food products are well known in the art,see, e.g., U.S. Pat. No. 6,403,142, and include dog food, cat food,rabbit food, and the like. The animal food product may also be foodproducts useful for feeding livestock, such as cattle, bison, pigs,chicken, and the like. In another embodiment, the animal foodcomposition of the present invention is a solid hypoallergenic pet foodcomprising a component that contains protein or protein fragmentswherein all of said component is partially hydrolyzed and furthercomprises one or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above.

Additionally, the invention is directed to a process of preparing animproved animal food product, wherein the improvement comprises addingone or more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, to ananimal food product. In certain embodiments, the one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, are added to an animal food productin an amount of about 1% to about 25%, about 1% to about 10%, or about5%, 10%, or 15%, by weight.

In one embodiment, the pharmaceutical composition comprises one sweettastant. In another embodiment, the pharmaceutical composition comprisesmore than one sweet tastant. In certain embodiments, the pharmaceuticalcomposition comprises sucrose and corn syrup, or sucrose and aspartame,or saccharin and sucralose as sweet tastants. In another embodiment, thepharmaceutical composition contains a sweet tastant selected from sugar,(sucrose), dextrose, maltose, dextrin, dried invert sugar, fructose,levulose, lactose, galactose, corn syrup, malodextrin, honey, sugaralcohols such as sorbitol, mannitol, xylitol, lactitol, malitol,hydrogenated starch hydrolysates, maltitol and the like, thaumatin,aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl maltol,glycine, isomalt, spray dried licorice root, glycyrrhizin, sodiumgluconate, glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®,EQUAL®, SWEET 'N LOW®, and NUTRASWEET®.

In each of the embodiments of the compositions described herein, acompound of Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, may be used in varying ratios to theagent that is believed to cause the sweet taste. The compound accordingto Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, can be typically present in an amount rangingfrom about 0.001% to about 50% by weight, preferably about 0.1% to about10% by weight, or alternatively, from 0.1% to about 1% by weight. Thepresent invention also contemplates an amount of about 1% to about 20%,preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of thefood product.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the food product.

In each of the embodiments of the methods described herein, a compoundof Formula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used in varying ratios to the tastant,i.e. the agent that is believed to cause the sweet taste. For example, acomposition of the invention may comprise a compound of Formula I in amolar ratio of about 0.001:1 to about 10:1, or alternativelyadministered in a molar ratio of about 0.01:1, about 0.02:1, about0.05:1, about 0.1:1, or about 0.5:1, relative to the tastant. As will beappreciated, the various ranges and amounts of the compound of Formula Ican be used, with modifications if preferred, in each of the embodimentsdescribed herein.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in the food product in an amount ranging from about 0.001 mg toabout 10 g per serving, preferably about 0.01 mg to about 5 g perserving, or alternatively, from 0.05 mg to about 1 g per serving. Thepresent invention also contemplates food products with amounts of thecompound of Formula I of about 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 500 mg, 1 g, 2 g, 5 g and 8 g per serving.

The sweet taste of the food product may be enhanced by the compound ofFormula I is enhanced by at least about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, or 95%, or from about 60% to about 99%, or alternativelyfrom about 20% to about 50%. Thus, in a more specific embodiment,composition comprising a food product comprising a sweet tastant, one ormore food ingredients, and one or more compounds according to Formula I,wherein the one or more compounds according to Formula I are present inan amount sufficient to enhance a sweet taste, produced by the foodproduct, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 95%, or from about 60% to about 99%, or alternatively from about 30%to about 70%. Of course, in other embodiments, the sweetness may beenhanced to differing extents.

Any amount of the compound of Formula I that provides the desired degreeof sweetness enhancement can be used. For example, a compound of FormulaI may be used at a concentration of about 0.1 μM to about 5,000 μM toenhance a sweet taste. Alternatively, concentrations of about 1 μM, 100μM, or 500 μM of a compound of Formula I may be used to enhance a sweettaste.

In one aspect, the present invention is directed to a pharmaceuticalcomposition comprising a compound of Formula I, as defined above,including any of the specific embodiments, subclasses, or speciesdescribed above, and one or more pharmaceutically acceptable carriers.Preferred compositions of the present invention are pharmaceuticalcompositions comprising a compound selected from one or more embodimentslisted above, and one or more pharmaceutically acceptable excipients.Pharmaceutical compositions that comprise one or more compounds ofFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, may be used to formulate pharmaceutical drugscontaining one or more active agents that exert a biological effectother than sweetness enhancement.

In one embodiment, the pharmaceutical composition comprises one sweettastant. In another embodiment, the pharmaceutical composition comprisesmore than one sweet tastant. In certain embodiments, the pharmaceuticalcomposition comprises sucrose and corn syrup, or sucrose and aspartame,or saccharin and sucralose as sweet tastants. In another embodiment, thepharmaceutical composition contains a sweet tastant selected from sugar,(sucrose), dextrose, maltose, dextrin, dried invert sugar, fructose,levulose, lactose, galactose, corn syrup, malodextrin, honey, sugaralcohols such as sorbitol, mannitol, xylitol, lactitol, malitol,hydrogenated starch hydrolysates, maltitol and the like, thaumatin,aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl maltol,glycine, isomalt, spray dried licorice root, glycyrrhizin, sodiumgluconate, glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA®,EQUAL®, SWEET 'N LOW®, and NUTRASWEET®.

The pharmaceutical composition preferably further comprises one or moreactive agents that exert a biological effect. Such active agentsincludes pharmaceutical and biological agents that have an activityother than taste enhancement. Such active agents are well known in theart. See, e.g., The Physician's Desk Reference. Such compositions can beprepared according to procedures known in the art, for example, asdescribed in Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa., USA. In one embodiment, such an active agent includesbronchodilators, anorexiants, antihistamines, nutritional supplements,laxatives, analgesics, anesthetics, antacids, H₂-receptor antagonists,anticholinergics, antidiarrheals, demulcents, antitussives,antinauseants, antimicrobials, antibacterials, antifungals, antivirals,expectorants, anti-inflammatory agents, antipyretics, and mixturesthereof. The pharmaceutical composition according to the presentinvention may comprise one or more compounds according to Formula I, asdescribed above, or any of the specific subgroups, subclasses, orspecific compounds described above; an active agent that has a bittertaste; and optionally one or more pharmaceutically acceptable carriers.

In another embodiment, the active agent is selected from the groupconsisting of antipyretics and analgesics, e.g., ibuprofen,acetaminophen, or aspirin; laxatives, e.g., phenolphthalein dioctylsodium sulfosuccinate; appetite depressants, e.g., amphetamines,phenylpropanolamine, phenylpropanolamine hydrochloride, or caffeine;antacidics, e.g., calcium carbonate; antiasthmatics, e.g., theophylline;antidiuretics, e.g., diphenoxylate hydrochloride; agents active againstflatulence, e.g., simethecon; migraine agents, e.g., ergotaminetartrate;psychopharmacological agents, e.g., haloperidol; spasmolytics orsedatives, e.g., phenobarbitol; antihyperkinetics, e.g., methyldopa ormethylphenidate; tranquilizers, e.g., benzodiazepines,hydroxinmeprobramates or phenothiazines; antihistaminics, e.g.,astemizol, chloropheniramine maleate, pyridamine maleate, doxlaminesuccinate, bromopheniramine maleate, phenyltoloxamine citrate,chlorocyclizine hydrochloride, pheniramine maleate, and phenindaminetartrate; decongestants, e.g., phenylpropanolamine hydrochloride,phenylephrine hydrochloride, pseudoephedrine hydrochloride,pseudoephedrine sulfate, phenylpropanolamine bitartrate, and ephedrine;beta-receptor blockers, e.g., propanolol; agents for alcohol withdrawal,e.g., disulfuram; antitussives, e.g., benzocaine, dextromethorphan,dextromethorphan hydrobromide, noscapine, carbetapentane citrate, andchlophedianol hydrochloride; fluorine supplements, e.g., sodiumfluoride; local antibiotics, e.g., tetracycline or cleocine;corticosteroid supplements, e.g., prednisone or prednisolone; agentsagainst goiter formation, e.g., colchicine or allopurinol;antiepileptics, e.g., phenyloine sodium; agents against dehydration,e.g., electrolyte supplements; antiseptics, e.g., cetylpyridiniumchloride; NSAIDs, e.g., acetaminophen, ibuprofen, naproxen, or saltsthereof; gastrointestinal active agents, e.g., loperamide andfamotidine; various alkaloids, e.g., codeine phosphate, codeine sulfate,or morphine; supplements for trace elements, e.g., sodium chloride, zincchloride, calcium carbonate, magnesium oxide, and other alkali metalsalts and alkali earth metal salts; vitamins; ion-exchange resins, e.g.,cholestyramine; cholesterol-depressant and lipid-lowering substances;antiarrhythmics, e.g., N-acetylprocainamide; and expectorants, e.g.,guaifenesin.

Active substances which have a particularly unpleasant taste includeantibacterial agents such as ciprofloxacin, ofloxacin, and pefloxacin;antiepileptics such as zonisamide; macrolide antibiotics such aserythromycin; beta-lactam antibiotics such as penicillins andcephalosporins; psychotropic active substances such as chlorpromazine;active substances such as sulpyrine; and agents active against ulcers,such as cimetidine.

In another embodiment, the pharmaceutical composition comprises one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, and at least oneamino acid selected from the group consisting of glycine, L-alanine,L-arginine, L-aspartic acid, L-cystine, L-glutamic acid, L-glutamine,L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine,L-ornithine, L-phenylalanine, L-proline, L-serine, L-threonine,L-tryptophan, L-tyrosine, L-valine, creatine, and mixtures thereof.

In another embodiment, the pharmaceutical composition comprises one ormore compounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above; a biologically activeagent that exhibits an activity other than sweetness enhancement; and atleast one amino acid, such as one selected from the group consisting ofglycine, L-alanine, L-arginine, L-aspartic acid, L-cystine, L-glutamicacid, L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine,L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine,L-threonine, L-tryptophan, L-tyrosine, L-valine, creatine, and mixturesthereof.

The pharmaceutical compositions of the present invention can be in anyform suitable to achieve their intended purpose. Preferably, however,the composition is one which can be administered buccally or orally.Alternatively, the pharmaceutical composition may be an oral or nasalspray.

The pharmaceutical compositions of the invention can be in any formsuitable for administration to any animal that can experience thebeneficial effects of one or more compounds according to Formula I, orany of the specific subgroups, subclasses, or specific compoundsdescribed above. Foremost among such animals are humans, although theinvention is not intended to be so limited. Other suitable animalsinclude canines, felines, dogs, cats, livestock, horses, cattle, sheep,and the like. A veterinary composition, as used herein, refers to apharmaceutical composition that suitable for non-human animals. Suchveterinary compositions are known in the art.

The pharmaceutical preparations of the present invention can bemanufactured using known methods, for example, by means of conventionalmixing, granulating, dragée-making, dissolving, or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Pharmaceutical excipients are well known in the art. Suitable excipientsinclude fillers such as saccharides, for example, lactose or sucrose,mannitol or sorbitol, cellulose preparations and/or calcium phosphates,for example, tricalcium phosphate or calcium hydrogen phosphate, as wellas binders, such as, starch paste, using, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,and/or polyvinyl pyrrolidone. If desired, disintegrating agents can beadded, such as, the above-mentioned starches and alsocarboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, oralginic acid or a salt thereof, such as, sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as, magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragée cores areprovided with suitable coatings that, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions canbe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations, such as, acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

In a further embodiment, the invention is directed to a chewable tabletcomprising a sweet tastant and one or more compounds according toFormula I and one or more biologically active agents. Chewable tabletsare known in the art. See, e.g., U.S. Pat. Nos. 4,684,534 and 6,060,078,each of which is incorporated by reference in its entirety. Any kind ofmedicament may be contained in the chewable tablet, preferably amedicament of bitter taste, natural plant extracts or other organiccompounds. More preferably, vitamins such as vitamin A, vitamin B,vitamin B₁, vitamin B₂, vitamin B₆, vitamin C, vitamin E and vitamin K;natural plant extracts such as Sohgunjung-tang extracts,Sipchundaebo-tang extracts and Eleutherococcus senticosus extracts;organic compounds such as dimenhydrinate, meclizine, acetaminophen,aspirin, phenylpropanolamine, and cetylpyridinium chloride; orgastrointestinal agents such as dried aluminum hydroxide gel,domperidone, soluble azulene, L-glutamine and hydrotalcite may becontained in the core.

In another embodiment, the present invention is directed to an orallydisintegrating composition wherein said orally disintegratingcomposition comprises a sweet tastant and one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above. Orally disintegrating tablets areknown in the art. See, e.g., U.S. Pat. Nos. 6,368,625 and 6,316,029,each of which is hereby incorporated by reference in its entirety.

In another embodiment, the present invention is further directed to anasal composition comprising a sweet tastant and one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above. Nasal sprays are known in the art.See, e.g., U.S. Pat. No. 6,187,332. Addition of one or more compoundsaccording to Formula I to a nasal spray can reduce the experience of anunpleasant taste associated with the composition of the nasal spray. Byway of a nonlimiting example, a nasal spray composition according to thepresent invention comprises water (such as 95-98 weight percent), acitrate (such as 0.02 M citrate anion to 0.06 M citrate anion), acompound according to Formula I, and optionally phosphate (such as 0.03M phosphate to 0.09 M phosphate).

In another embodiment, the present invention is directed to a soliddosage form comprising a sweet tastant and a water and/or salivaactivated effervescent granule, such as one having a controllable rateof effervescence, and a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above.The effervescent composition may further comprise a pharmaceuticallyactive compound. Effervescent pharmaceutical compositions are known inthe art. See, e.g., U.S. Pat. No. 6,649,186, which is incorporated byreference in its entirety. The effervescent composition can be used inpharmaceutical, veterinary, horticultural, household, food, culinary,pesticidal, agricultural, cosmetic, herbicidal, industrial, cleansing,confectionery and flavoring applications. Formulations incorporating theeffervescent composition comprising a compound according to Formula Ican further include one or more additional adjuvants and/or activeingredients which can be chosen from those known in the art includingflavors, diluents, colors, binders, filler, surfactant, disintegrant,stabilizer, compaction vehicles, and non-effervescent disintegrants.

In another embodiment, the present invention is directed to afilm-shaped or wafer-shaped pharmaceutical composition that comprises asweet tastant and a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,and is capable of disintegrating. Such a film-shaped or wafer-shapedpharmaceutical composition can be configured, for example, as quicklydisintegrating administration forms, e.g., administration formsdisintegrating within a period of 1 second up to 3 minutes, or as slowlydisintegrating administration forms, e.g., administration formsdisintegrating within a period of 3 to 15 minutes.

The indicated disintegration times can be set to the above-mentionedranges by using, for example, matrix-forming polymers which havedifferent disintegrating, or solubility, characteristics. Thus, bymixing the corresponding polymer components, the disintegration time canbe adjusted. In addition, disintegrants are known which “draw” waterinto the matrix and cause the matrix to burst open from within. As aconsequence, certain embodiments of the invention include suchdisintegrants for the purpose of adjusting the disintegration time.

Suitable are polymers for use in the film-shaped or wafer-shapedpharmaceutical composition include cellulose derivatives, polyvinylalcohol (e.g. MOWIOL™) polyacrylates, polyvinyl pyrrolidone, celluloseethers, such as ethyl cellulose, as well as polyvinyl alcohol,polyurethane, polymethacrylates, polymethyl methacrylates andderivatives and copolymerisates of the aforementioned polymers.

In certain embodiments, the total thickness of the film-shaped orwafer-shaped pharmaceutical composition according to the invention ispreferably 5 mm up to 10 mm, preferably 30 μm to 2 mm, and withparticular preference 0.1 mm to 1 mm. The pharmaceutical preparationsmay round, oval, elliptic, triangular, quadrangular or polygonal shape,but they may also have any rounded shape.

In another embodiment, the present invention is directed to acomposition comprising a sweet tastant, a medicament or agent containedin a coating that surrounds a gum base formulation and asweetness-enhancing amount of a compound according to Formula I, or anyof the specific subgroups, subclasses, or specific compounds describedabove. Preferably, the coating comprises at least 50% by weight of theentire product. As the center is chewed, the medicament or agent isreleased into the saliva. For example, U.S. Pat. No. 6,773,716, which isincorporated herein by reference in its entirety, discloses a suitablemedicament or agent contained in a coating that surrounds a gum baseformulation. One or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,can be used in preparing the coating. Optionally, the composition mayfurther comprise high-intensity sweeteners and appropriate flavors. Ithas been found that with respect to certain medicaments or agents thatmay have an astringent or bitter taste that by adding a sweetenerenhancing agent to the formulation, that a much more palatableformulation, including the medicament, can be provided. In this regard,even though the medicament in, for example, its powder form may bebitter or have an offensive taste, the matrix used as the coating of thepresent invention, including the enhancing agent, will afford a producthaving acceptable medicinal properties. The compound according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above, can be typically present in an amount rangingfrom about 0.001% to about 50% by weight, preferably about 0.1% to about10% by weight, or alternatively, from 0.1% to about 1% by weight. Thepresent invention also contemplates an amount of about 1% to about 20%,preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of thepharmaceutical composition.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the pharmaceutical composition.

In yet another embodiment, the present invention is directed to aprocess of preparing an improved composition comprising a medicament oragent contained in a coating that surrounds a gum base formulation,wherein the improvement comprises adding a compound according to FormulaI, or any of the specific subgroups, subclasses, or specific compoundsdescribed above, to the coating that surrounds the gum base formulation.The compound according to Formula I may be added in varying amounts,such as about 30% 50%, 75%, 80%, or 90%, or from about 10% to about 90%.In other embodiments, the compound according to Formula I is present inabout 1% to about 30%.

In a further embodiment, the invention is directed to a pharmaceuticalcomposition suitable for aerosol administration, comprising a sweettastant and a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, and asuitable carrier. The aerosol composition may further comprisespharmaceutically active agent. Aerosol compositions are known in theart. See, e.g., U.S. Pat. No. 5,011,678, which is hereby incorporated byreference in its entirety. As a nonlimiting example, an aerosolcomposition according to the present invention may comprise a medicallyeffective amount of a pharmaceutically active substance, one or morecompounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, and a biocompatiblepropellant, such as a (hydro/fluoro)carbon propellant.

In certain embodiments, the pharmaceutical compositions of the inventioncomprise from about 0.001 mg to about 1000 mg of a compound of FormulaI, or any of the specific subgroups, subclasses, or specific compoundsdescribed above. In another embodiment, the compositions of theinvention comprise from about 0.01 mg to about 10 mg of a compound ofFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above.

In another embodiment, the composition of the invention comprises acompound of Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, in an amount sufficient to enhancethe sweet taste of a modulating protein. By way of example, the presentinvention is pharmaceutical or veterinary composition, comprising acompound of Formula I, or any of the specific subclasses and specificcompounds listed above, in an amount sufficient to enhance the tastemodulating protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, or 95%, or from about 50% to about 99%, or alternatively fromabout 10% to about 40%. In another embodiment, the present invention isdirected to a method of enhancing a sweet taste modulating protein,comprising contacting said taste modulating protein with a compound ofFormula I, or any of the specific subclasses and specific compoundslisted above, and inhibiting the protein by at least about 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about99%, or alternatively from about 20% to about 60%, and wherein saidtaste modulating protein is a naturally occurring taste modulatingprotein. In another embodiment, the present invention is directed to amethod of enhancing a taste modulating protein, comprising contactingsaid protein with a compound of Formula I, or any of the specificsubclasses and specific compounds listed above, and inhibiting theprotein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 95%, or from about 50% to about 99%, or alternatively from about 20%to about 40%, and wherein said protein is a naturally occurring humantaste modulating protein.

In another embodiment, the present invention is directed to anutritional composition comprising one or more nutritional, one or morecompounds according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, and optionally one ormore carriers. Examples of nutritional compositions having anundesirable taste include, but are not necessarily limited to, enteralnutrition products for treatment of nutritional deficit, trauma,surgery, Crohn's disease, renal disease, hypertension, obesity and thelike, to promote athletic performance, muscle enhancement or generalwell being or inborn errors of metabolism such as phenylketonuria. Inparticular, such nutritional formulations may contain one or more aminoacids which have a bitter or metallic taste or aftertaste. Such aminoacids include, but are not limited to, an essential amino acids selectedfrom the group consisting of L isomers of leucine, isoleucine,histidine, lysine, methionine, phenylalanine, threonine, tryptophan,tyrosine, and valine. Additionally, the invention is directed to aprocess of preparing an improved nutritional composition, wherein theimprovement comprises adding one or more compounds according to FormulaI, or any of the specific subgroups, subclasses, or specific compoundsdescribed above, to a nutritional composition. In certain embodiments,the one or more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, are addedto a nutritional composition in an amount of about 1% to about 50%, orabout 5%, 10%, or 15%, by weight.

In another embodiment, the present invention is directed to a dentalhygienic composition comprising one or more compounds according toFormula I, or any of the specific subgroups, subclasses, or specificcompounds described above. Dental hygienic compositions are known in theart and include but are not necessarily limited to toothpaste,mouthwash, plaque rinse, dental floss, dental pain relievers (such asAnbesol™), and the like.

Additionally, the invention is directed to a process of preparing animproved dental hygienic composition, wherein the improvement comprisesadding one or more compounds according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,to a dental bleaching composition. In certain embodiments, the one ormore compounds according to Formula I are added to a dental hygieniccomposition in an amount of about 0.001% to about 50% by weight,preferably about 0.1% to about 10% by weight, or preferably, from 0.1%to about 1% by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the dental hygienic composition.

In another embodiment, the present invention is directed to a cosmeticproduct comprising one or more compounds according to Formula I, or anyof the specific subgroups, subclasses, or specific compounds describedabove. For example, but not by way of limitation, the cosmetic productcomprising a compound according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, may be aface cream, lipstick, lip gloss, and the like. Other suitablecompositions of the invention include lip balm, such as CHAPSTICK® orBURT'S BEESWAX® Lip Balm, further comprising one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above.

Additionally, the invention is directed to a process of preparing animproved cosmetic product, wherein the improvement comprises adding oneor more compounds according to Formula I, or any of the specificsubgroups, subclasses, or specific compounds described above, to acosmetic product. In certain embodiments, the one or more compoundsaccording to Formula I, or any of the specific subgroups, subclasses, orspecific compounds described above, are added to a cosmetic product inan amount of about 1% to about 20%, preferably about 1% to about 5%, orabout 1%, 2%, or 3%, by weight.

The compound according to Formula I, or any of the specific subgroups,subclasses, or specific compounds described above, can be typicallypresent in an amount ranging from about 0.00001% to about 50% by weight,preferably about 0.0001% to about 2% by weight, or alternatively, from0.0001% to about 0.1% by weight. The present invention also contemplatesan amount of about 0.0001% to about 1%, preferably about, 0.0005%,0.001%, 0.002%, 0.005%, 0.01%, 0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight,of the cosmetic product.

The activity of a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described abovecan be determined by testing said compound using a number of methodsknown in the art. For example, one can evaluate the ability of acompound to enhance a sweet taste by using an in vivo taste assay.

The activity of a compound according to Formula I, or any of thespecific subgroups, subclasses, or specific compounds described above,can also be determined by means of the assay described below.

Methods of Preparation of Compounds

A compound according to Formula I can be synthesized according tomethods outlined in the following descriptions. The compounds for use inthe present invention can be synthesized using procedures known in theart.

The following general schemes illustrate synthetic methods that can beused to prepare compounds of the present invention. In one process, acompound of Formula I can be prepared by condensing a suitableoptionally substituted thiophene, pyrrole, imidazole or thiazole halidewith a suitable hydroxypyridine or thiopyridine in a suitable organicsolvent, as shown in Scheme 1 (wherein G¹ is N or S; X is halogen, suchas a bromo group; A is S or O; n is between 0 and 4; R⁴ is selected fromNO₂, halogen, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl; and G³, R¹, R², and R³ aredefined as above).

For instance, this reaction can be used to prepare the compound ofExample 3 by reacting methyl 3-bromothiophene-2-carboxylate with2-hydroxy-5-nitropyridine according to Scheme 2.

The compound of Example 8 can be prepared by reacting 1-ethyl-2-methyl,4-nitro-5-bromoimidazole and 2-thio-5-chloropyridine according to Scheme3.

As a further example, compounds of Formula I, wherein R¹ and R² togetherwith G₃ and the carbon atom to which R¹ is attached form a heterocycle,can be prepared by a direct condensation of an alpha-halo aldehyde orketone with an amino heterocycle in a reaction medium containing asuitable solvent according to Scheme 4 (wherein G₁, G₂, G₃, R², R³, R⁴are as defined above; R⁵ is selected from H, C₁₋₆ alkyl, and optionallysubstituted phenyl; R⁶ is selected from H and C₁₋₆ alkyl; and X is ahalogen, preferably bromine).

For example, the compound of Example 5 can be prepared by reacting2-aminothiadiazole with bromo-benzaldehyde according to Scheme 5.

As a further example, the Compounds of Formula I wherein R³ is an etheror thioether can be prepared by reacting suitable optionally substitutedthiophene, pyrrole, imidazole or thiazole with an appropriate alkylhalide in a suitable organic solvent according to Scheme 6 (wherein G₁,G₂, G₃, R¹, R², R⁴, R⁵ and R⁶ are as defined above; and X is a halogen,preferably bromine; Q₁ and Q₂ are independently selected from S or O; nis 0 to 4; R⁷ is H, C₁₋₆ alkyl, C₁₋₆ alkenyl, or optionally substitutedphenyl). The reaction mixture is heated and filtered to give the desiredproduct.

For example, the compound of Example 2 can be prepared by according toScheme 7 in one step by a direct condensation of2-thiol-aminobenzodithione in a 1:1 reaction medium.

The compound of Example 7 can also be prepared by this method as Scheme8 illustrates.

Compounds of Formula I wherein R³ is ═N—CH₂—(C=Q)-R⁷, wherein Q isselected from S or O; and R⁷ is H, C₁₋₆ alkyl or C₁₋₆ alkenyl, can beprepared by reacting an isothiocyanate or isocyanate with an imine in asuitable organic solvent, according to Scheme 9. The mixture is keptunder reduced pressure, and the desired product is precipitated out ofthe reaction mixture. It is then filtered off and dried to give anoff-white solid.

In particular, the compound of Example 10 is prepared fromallyisothiocyanate and 1-imino-compound according to Scheme 10.

The compounds of Formula I, wherein R³ is ═N—(CH₂)—(C═O)—OR⁷ (wherein nis 0 to 4; and R⁷ is C₁₋₆ alkyl, or C₁₋₆ alkenyl) can be preparedaccording to Scheme 11.

The iminio compound and haloalkyl ester are heated together in asuitable organic solvent for a brief period of time. The contents arethen allowed to cool down, and the material is allowed to settle down.The cooled down material is then filtered.

This method can be used to prepare the Compound of Example 1 by reactingethyl 2-bromoacetate with an iminiothiomethyl compound according toScheme 12.

Similarly other compounds of this invention can be obtained fromcommercial sources and prepared by those skilled in the art. Startingmaterials are commercially available or they can be prepared by ordinarypersons trained in the art.

The following examples are illustrative, but not limiting, of themethod, compounds, and compositions of the present invention. Each ofthe compounds listed below was obtained from commercially availablecatalog companies, such as Aldrich RarechemLib, Aldrich Sigma, AsInEx,Bionet, Biotech Corp., Brandon/Berlex, Calbiochem, ChemBridge, ComgenexWest, Foks H, G. & J. Research, IBS, ICN Biochemicals, Institute forChemotherapy, IF Ltd., Kodak, Lederle Labs, Ligand-CGX, Maybridge PRI,Menai Organics, Menai/Neurocrine, MicroSource, MPA Chemists,Mybrgd/ONYX, PRI-Peakdale, RADIAN, Receptor Research, RGI,Rhone-Poulenc, SPECS/BioSPECS/SYNTHESIA, T. Glinka, Tripos Modem, VWR,Zaleska, Zelinksy/Berlex, Aeros, and Chemica. The compounds werepurified using conventional purification procedures, such as HPLC. Theidentity of the compound was confirmed using HPLC and mass spectrometry.Other suitable modifications and adaptations of the variety ofconditions and parameters normally encountered and obvious to thoseskilled in the art are within the spirit and scope of the invention.

EXAMPLES Example 1 Ethyl2-(3-Methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate

Molecular Formula: C₁₂H₁₄N₂O₂S; m/z: 251 (M+H, found), 250 (calculated).

Example 2 2-(2-(2-Methoxyphenoxy)ethylthio)-1H-benzimidazole

Molecular Formula: C₁₆H₁₅N₂O₂S; m/z: 301, (M+H, found), 300(calculated).

Example 3 Methyl 3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate)

Molecular Formula: C₁₁H₈O₅N₂S; m/z: 281 (M+H, found), 280 (calculated).

Example 46-(4-Chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole

Molecular Formula: C₁₁H₉N₆O₂Cl; m/z: 292 (calculated).

Example 5 6-p-Tolylimidazo[2,1-b][1,3,4]thiadiazole

Molecular Formula: C₁₁H₉N₃S; m/z: 216 (M+H, found), 215 (calculated).

Example 6N-Phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide

Molecular Formula: C₂₀H₂₁ON₅S; m/z: 379 (calculated).

Example 72-(2-(2-(2,6-Dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol

Molecular Formula: C₁₉H₂₂O₂N₄S; m/z: 374 (calculated).

Example 8 1-Ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole

Molecular Formula: C₁₁H₁₁O₂ClS; m/z: 298 (calculated), 299 (M+H, found).

Example 9 2,4-Diphenyl-5,5-dimethylimidazole-1-oxide

Molecular Formula: C₁₇H₁₆N₂O; m/z: 264 (calculated).

Example 10 1-Allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea

Molecular Formula: C₁₂H₁₃N₃S₂; m/z: 264 (M+H, found), 263 (calculated).

Example 11 2-(2-Iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone

Molecular Formula: C₁₁H₉N₃O₃; m/z: 263 (calculated).

Example 12 4-Phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one

Molecular Formula: C₁₈H₁₉N₃O₂S; m/z: 341 (calculated).

Example 13 2-(3-Chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine

Molecular Formula: C₁₄H₁₁N₂OCl; m/z: 258 (calculated).

Example 14 N-(4-(4-Ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide

Molecular Formula: C₂₀H₂₀N₂O₃S; m/z: 368 (calculated).

Example 15 1-Phenylthiochromeno[4,3-d]imidazol-4(1H)-one

Molecular Formula: C₁₆H₁₀N₂OS; m/z: 278 (calculated).

Example 16 N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide

Molecular Formula: C₁₃H₁₄N₃OSCl; m/z: 295 (calculated).

Example 175-Chloro-1-methyl-3-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxamide

Molecular Formula: C₁₃H₈F₆N₃OCl; m/z: 371 (calculated).

Example 18N-(4-(((2,6-Dimethoxypyrimidin-4-yl)amino)sulfonyl)phenyl)-4-nitrobenzamide

Molecular Formula: C₁₉H₁₇N₅O₇S; m/z: 461 (found), 459 (calculated).

Example 19 4-Phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one

Molecular Formula: C₁₉H₁₉N₃O; m/z: 305 (calculated).

Example 20 5-(Perfluorophenoxy)isophthalic acid

Molecular Formula: C₁₄H₅F₅O₅; m/z: 348 (calculated).

Example 21 2-(Dibenzylamino)acetic acid

Molecular Formula: C₁₅H₁₇O₂N; m/z: 255 (calculated).

Example 22 Ethyl 2-cyano-2-(phenyldiazenyl)acetate

Molecular Formula: C₁₁H₁₁N₃O₂; m/z: 217 (calculated).

Activity of Selected Compounds

TRPM5 is an ion channel that is a part of the taste-perceptionmachinery. This ion channel has been shown to be essential for tastetransduction. Perez et al., Nature Neuroscience 5:1169-1176 (2002);Zhang et al., Cell 112:293-301 (2003). Because TRPM5 is a necessary partof the taste-perception machinery, enhancement of its activity couldenhance the sensation of particular tastes.

Taste is the ability to respond to dissolved molecules and ions calledtastants. Humans detect taste with taste receptor cells, which areclustered in taste buds. (Kinnamon, S. C. TINS 11:491-496 (1988)).Tastants bind specific receptors on the cell membrane of a tastereceptor cell, leading to a voltage change across the cell membrane. Achange in voltage across the cell membrane depolarizes, or changes theelectric potential of the cell. This leads to a signal being sent to asensory neuron leading back to the brain.

TRPM5 is a member of the transient receptor potential (TRP) family ofion channels. Ion channels are transmembrane proteins that form pores ina cell membrane and allow ions to pass from one side to the other(reviewed in B. Hille (Ed), 1992, Ionic Channels of Excitable Membranes2nd ed., Sinauer, Sunderland, Mass.). Many channels have “gates” thatopen in response to a specific stimulus. As examples, voltage-gatedchannels respond to a change in the electric potential across themembrane, mechanically-gated channels respond to mechanical stimulationof the membrane, and ligand-gated channels respond to the binding ofspecific molecules. Various ligand-gated channels can open in responseto extracellular factors, such as a neurotransmitters (transmitter-gatedchannels), or intracellular factors, such as ions (ion-gated channels),or nucleotides (nucleotide-gated channels). Still other ion channels aremodulated by interactions with other proteins, such as G-proteins(G-protein coupled receptors or GPCRs).

Most ion channels mediate the permeation of one predominant ionicspecies. For example, sodium (Na⁺), potassium (K⁺), chloride (CF), andcalcium (Ca²⁺) channels have been identified. While TRPM5 has beencharacterized as a non-selective monovalent cation channel, Prawitt etal., Proc. Nat. Acad. Sci. USA 100:15166-71 (2003), physiologically itis thought to primarily conduct sodium, the most abundant cation inextracellular fluids.

TRPM5 is believed to be activated by stimulation of a receptor pathwaycoupled to phospholipase C and by IP3-mediated Ca²⁺ release. The openingof this channel is dependent on a rise in Ca²⁺ levels. Hofmann et al.,Current Biol. 13:1153-1158 (2003). The activation of this channel leadsto depolarization of the TRC, which in turn leads to transmitter releaseand excitation of primary gustatory nerve fibers. Huang, et al., Proc.Nat. Acad. Sci. USA 104: 6436-6441 (2007).

The activity of human TRPM5 ion channel was measured in live cells on afluorescent imaging plate reader (FLIPR). The basis of the assay (shownin FIG. 1) is the calcium-dependent activation of the ion channel whichoccurs via by activation of a G-protein coupled receptor (GPCR). GPCRactivation by an appropriate agonist causes a transient increase inintercellular Ca²⁺ ion concentration which in turn causes the ionchannel to open, letting in Na⁺ ions. This influx causes a change in themembrane potential of the cell which can be monitored as a change in thefluorescent signal from voltage-dependent (membrane potential)fluorescent dyes. A demonstration of the assay is shown in FIG. 2, wheretraces of fluorescent response (Ex 530 nm/Em565 nm) versus time areshown for cells containing the plasmid and sham plasmid controls. Whileall cells gave a Ca²⁺ response to the endogenous muscarinic GPCR agonistcarbachol (left panel), only cells containing the plasmid showed a sharppeak for the membrane potential dye response (right panel).

For the screening assay, the human TRPM5 gene was cloned, put intoHEK293 cells, and a stable, high expression clone was used forscreening. Cells were grown in standard media at 37° C. The day beforescreening, the cells were removed from flasks and added to 384 wellclear bottom plates (8K cells in 20 μL/well). On the assay day, 20 μL ofmembrane potential dye (Part No. 88123, Molecular Devices Corp.) wasadded to the cells and dye was allowed to be taken up, i.e., load, intothe cells for 1 hr at 37° C. The dye-loaded cell plate was placed in theFLIPR along with a second 384 well plate containing test compounds aswell as positive (fully inhibited) and negative (non-inhibited)controls. The assay was started by addition of 10 μL of solution fromthe compound plate into the cell plate. During this process, continuousfluorescent recordings were made simultaneously for all wells. Afteraddition of the compound solution, the tips were automatically washedand a stimulation solution of 3 μM ATP to activate TRPM5 (an agonist foran endogenous purinurgic GPCR), was added to all wells of the cellplate. The height of the response was calculated and percent inhibitionor enhancement values, versus negative control wells, was calculated forthe test samples. Exemplary results are shown in the upper left graph ofFIG. 3.

Two counterscreen assays were run on separate cell plates utilizing thesame cells as described above. In the calcium counterscreen, the cellswere loaded with a calcium sensitive dye (Calcium3 Dye, Part no. 8090,Molecular Devices Corp.) and stimulated by ATP to check for compoundsthat block the GPCR-mediated calcium activation step. Exemplary resultsof this assay are shown in the lower left graph of FIG. 3. In the KClcounterscreen, cells are stimulated with 10 mM KCl instead of ATP tocheck for compounds that inhibit the membrane potential response byvirtue of being non-specific ion channel blockers or enhancers.Exemplary results are shown in FIGS. 3-5. The selective enhancementTRPM5 activity by the compounds of Examples 1-3,5,10 and 18 at lowconcentration of ATP, the G-protein coupled receptor ligand isillustrated in FIG. 4. The left graph of FIG. 4 shows the enhancementeffect of the addition of a compound of the invention at 30 micromolaron the ATP concentration-effect function for membrane potential inhTRPM5-HEK293 cells, as measured by the fluorescent assay describedherein. The right graph shows the lack of effect of the addition of acompound of the invention at 30 micromolar on ATP concentration-effectfunction for intracellular calcium in hTRPM5-HEK293 cells, as measuredin the fluorescent assays described herein.

FIG. 5 illustrates the selective enhancement of TRPM5 activity by thecompounds of Examples 1-3, 5, 10, and 18. In particular, enhancement ismost pronounced at low ATP concentrations.

Unless otherwise indicated, the data in the table below were determinedusing the three assays described above, providing percent inhibitiondata at 10 Stimulation or enhancement is seen as negative inhibition.

TRPM5 Calcium KCl Example No. Activity Counterscreen Counterscreen 1−139 −18 10 2 −136 19 −3 3 −113 11 17 4 −101 13 −32 5 −100 23 7 6 −98−69 16 7 −95 −15 −4 8 −76 −22 7 9 −73 −15 17 10 −73 0 1 11 −68 −12 21 12−62 −5 3 13 −57 9 −10 14 −55 10 −101 15 −48 −22 −9 16 −23 −25 −9 17 −164 −25

Example 23 Electrophysiological Results

Standard whole-cell recordings were obtained from HEK 393 cells stablytransfected with human TRPM5. Internal solution contained 135 mMCsGlutamate, 10 mM HEPES, 2 mM MgATP, 5 mM CaCl₂ and 10 mM EGTA.External solution was HBSS (Gibco) buffered with 20 mM HEPES to pH 7.2.Currents were recorded with Multiclamp 700B amplifier using PClampsoftware; filtered at 1 kHz, sampled at 5 kHz. Holding potential was −80mV. TRPM5 current in a single was activated by intracellular calciumdialysis (free calcium) and sampled with 200 ms ramps from −80 to 80 mVat 1 Hz. Current amplitudes were measured at −80 and 80 mV and plottedversus time. FIG. 6 shows stimulation of TRPM5 current when TRPM5transfected cells are treated with 10 μM of the compound of Example 10applied in a flow-through chamber such that exposure of the cell to thecompound can be quickly turned on and off. The left graph of FIG. 6shows no current activation by compound application in the absence ofcalcium. The central graph of FIG. 6 shows a large >5 nA current (+80mV) in response to compound at an otherwise suboptimal calciumconcentration of 300 nm. The far right graph shows a current activatedby compound exposures at 30 μm calcium. While there is furtherstimulation of the TRPM5 current by compound at 30 uM, it is not asdramatic as at 300 nn Ca++. In essence, it appears that the compoundmakes the TRPM5 responsive lower or weaker Ca++ signals than is normallythe case. Note that no significant current was seen in non-transfected,sham HEK cells (not shown).

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

1-19. (canceled)
 20. A composition comprising (a) a sweet tastant; and(b) a compound of Formula I:

or a physiologically acceptable salt thereof, wherein G¹, G², and G³ areindependently selected from N, S, and C; R¹ and R² are independentlyabsent or selected from the group consisting of C₁₋₆ alkoxycarbonyl,hydrogen, C₁₋₆ alkyl, halogen, nitro, optionally substituted C₆₋₁₄ aryl,optionally substituted 5-14 membered heteroaryl, Ar-Q, optionallysubstituted (CH₂)_(n)C(═O)—O—R^(2a), and optionally substituted(CH₂)_(n)C(═O)aryl, or R¹ and R², together with the G³ and the carbonatom to which R¹ is attached, form a C₆₋₁₄ aryl or 5- to 14-memberedheterocycle, each of which is optionally substituted with 1-3substituents independently selected from the group consisting of amino,hydroxy, nitro, halogen, cyano, thiol, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkenyloxy, optionally substitutedC₆₋₁₄ aryl; or if the bond to R¹ and/or R² is a double bond, then R¹ andR² are independently selected from ═NH and ═O; R³ is selected from thegroup consisting of H, C₁₋₆ haloalkyl, C₁₋₆ alkyl, oxo, ═NH, optionallysubstituted C₆₋₁₄ aryl, optionally substituted 5-14 memberedheterocycle, and L¹-R³¹; R⁴ is absent or is selected from the groupconsisting of H, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, and optionallysubstituted (CH₂)_(n)C(═O)aryl, or when the bond to R⁴ is a double bond,R⁴ is ═O; R⁵ is either absent or is selected from the group consistingof hydrogen, C₁₋₆ alkyl, and optionally substituted phenyl amide; R⁷ iseither absent or selected from the group consisting of H and C₁₋₆ alkyl;R^(2a) is C₁₋₆ alkyl; R³¹ is H, C₁₋₆ alkyl, C₁₋₆ alkenyl, optionallysubstituted phenyl, amino, C₁₋₆ alkylamino, or C₁₋₆ dialkylamino; L¹ isa linker selected from the group consisting of ═Z¹—(CH₂)_(n)—Z²—,-(Het)-C(O)—NH—, ═N—(CH₂)_(n)—C(═Z³)—Z⁴—, —NH—C(═O)—(CH₂)_(n)—,

Z¹ is selected from the group consisting of ═N, —NH, O, and S; Z² isabsent, O, S, C(═O), C(═S), —C(═O)—O, C(═S)—O, —C(═O)—NH— or —C(═S)—NH;Z³ is O or S; Z⁴ is O, S, or NH; Het is a 5- to 7-memberednitrogen-containing heterocycle; Q is CH₂, O, NH, or S; Ar is optionallysubstituted aryl or optionally substituted heteroaryl; and n is 0 to 10.21. The composition according to claim 20, wherein the compound ofFormula I is

or a physiologically acceptable salt thereof, wherein R³ is L¹-R³¹; R⁴is absent, H, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl; R⁵ is absent, H, or C₁₋₆alkyl; R^(a) is H or C₁₋₆ alkyl; and G¹ and G² are independently C, N,or S.
 22. The composition according to claim 20, wherein the compound ofFormula I is

or a physiologically acceptable salt thereof, wherein R⁴ is H, C₁₋₆alkyl, or C₁₋₆ hydroxyalkyl; R^(a) is H or C₁₋₆ alkyl; R³¹ is selectedfrom the group consisting of H, C₁₋₆ alkyl, and C₁₋₆ alkenyl; Z³ is O orS; Z⁴ is O, S, or NH; and n is 0 to
 3. 23. The composition according toclaim 20, wherein the compound of Formula I is

or a physiologically acceptable salt thereof, wherein R⁴ is selectedfrom the group consisting of H, C₁₋₆ alkyl, and C₁₋₆ hydroxyalkyl; R^(a)is H or C₁₋₆ alkyl; R^(b) is C₁₋₆ alkyl, C₁₋₆ alkyloxy, or hydroxy; n is0 to 3; and p is 0 to
 5. 24. The composition according to claim 20,wherein the compound of Formula I is

or a physiologically acceptable salt thereof, wherein G¹ is N or S; Q isN or C; R³ is H or optionally substituted phenyl; R⁵ is H when G¹ is N,or otherwise is absent; R⁶ is selected from the group consisting of Hand C₁₋₆ alkyl; and R⁷ is selected from the group consisting of H, C₁₋₆alkyl, and optionally substituted phenyl, or, when Q is N, R⁷ is absent.25. The composition according to claim 20, wherein the compound ofFormula I is

or a physiologically acceptable salt thereof, wherein R¹ and R² areindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S, or CH₂, and Ar is anoptionally substituted aryl or optionally substituted heteroaryl; R³ isH or C₁₋₆ alkyl; R⁴ is absent, H, or C₁₋₆ alkyl; R⁵ is absent, H, orC₁₋₆ alkyl; G¹ is C or N; and G² is N or S.
 26. The compositionaccording to claim 20, wherein Ar-Q is an optionally substituted 5-14membered heteroaryloxy or optionally substituted 5-14 memberedheteroarylthio.
 27. The composition according to claim 21, wherein thecompound is

or a physiologically acceptable salt thereof, wherein R³ is L¹-R³¹; R⁵is H or C₁₋₆ alkyl; G² is N or S; and R^(a) is H or C₁₋₆ alkyl.
 28. Thecomposition according to claim 21, wherein the compound of Formula I is:

or a physiologically acceptable salt thereof, wherein G¹ is S or N; R⁴is H, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl; R³¹ is H, C₁₋₆ alkyl, C₁₋₆alkenyl, or optionally substituted phenyl; R^(a) is H or C₁₋₆ alkyl; Z¹is S or N; Z² is —C(═O)—O—, —C(═S)—O, —O—, —S—, —C(═O)—NH—, or—C(═S)—NH—; and n is 0 to
 4. 29. The composition according to claim 24,wherein the compound is

or a physiologically acceptable salt thereof, wherein R³ is H, C₁₋₆alkyl, or optionally substituted phenyl; and R⁷ is selected from thegroup consisting of H, C₁₋₆ alkyl, and optionally substituted phenyl.30. The composition according to claim 20, wherein the compound is

or a physiologically acceptable salt thereof, wherein R³ is H or C₁₋₆alkyl; R⁵ is H or C₁₋₆ alkyl; Ar is a 5- to 10-membered aryl orheteroaryl group optionally substituted with one or more groupsindependently selected from the group consisting of NO₂, halogen, C₁₋₆alkyl, and C₁₋₆ hydroxyalkyl; Q is O or NH; R^(b) is H or C₁₋₆ alkyl;and n is 0 to
 3. 31. The composition according to claim 30, wherein thecompound is

or a physiologically acceptable salt thereof, wherein R³ is H or C₁₋₆alkyl; each occurrence of R^(a) is independently selected from the groupconsisting of NO₂, halogen, C₁₋₆ alkyl, or C₁₋₆ hydroxyalkyl; R^(b) is Hor C₁₋₆ alkyl; and n is 0 to
 3. 32. The composition according to claim20, wherein the compound is:

or a physiologically acceptable salt thereof, wherein R¹ is H, C₁₋₆alkyl, halogen, or NO₂; R³ and R⁴ are independently H or C₁₋₆ alkyl; Qis S, N, or O; and Ar is a 5- to 6-membered heteroaryl optionallysubstituted with one or more substituents independently selected fromthe group consisting of nitro and halogen.
 33. The composition accordingto claim 20, wherein the compound of Formula I is:

or a physiologically acceptable salt thereof, wherein R¹ and R³ areindependently optionally substituted phenyl; R⁴ is absent or C₁₋₆ alkyl;and R² and R⁷ are independently C₁₋₆ alkyl.
 34. The compositionaccording to claim 20, wherein the compound is

or a physiologically acceptable salt thereof, wherein R¹ is H or C₁₋₆alkyl; R² is H; R³ is C₁₋₆ alkyl, H, oxo, or ═NH; R³¹ is optionallysubstituted phenyl; and n is 0 to
 3. 35. The composition according toclaim 20, wherein the compound is:

or a physiologically acceptable salt thereof, wherein R¹ is H or C₁₋₆alkyl; R² is H or C₁₋₆ alkyl; R³³ is optionally substituted phenyl; R³⁴is H or C₁₋₆ alkyl; and m is
 1. 36. The composition according to claim20, wherein the compound is selected from the group consisting of ethyl2-(3-methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate;2-(2-(2-methoxyphenoxy)ethylthio)-1H-benzo[d]imidazole; methyl3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate;6-(4-chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole;6-p-tolylimidazo[2,1-b][1,3,4]thiadiazole;N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide;2-(2-(2-(2,6-dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol;1-ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole;2,4-diphenyl-5,5-dimethylimidazole-1-oxide;1-allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea;2-(2-iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone;3-benzyl-1-isopropyl-5-(4-methylthiazol-2-yl)pyrimidine-2,4(1H,3H)-dione;2-(3-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine;N-(4-(4-ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide;1-phenylthiochromeno[4,3-d]imidazol-4(1H)-one;N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;5-chloro-1-methyl-3-(trifluoromethyl)-N-(4-trifluoromethyl)phenyl)-1H-pyrazole-4-carboxamide;and physiologically acceptable salts thereof.
 37. The compositionaccording to claim 20, wherein the sweet tastant is selected from thegroup consisting of sucrose, fructose, and mixtures thereof.
 38. Thecomposition according to claim 37, wherein the compound according toFormula I and the sweet tastant are in a ratio from about 1:10⁶ to about1:10³.
 39. The composition according to claim 20, wherein saidcomposition further comprising an active agent and optionally one ormore pharmaceutically acceptable carriers.